Hexahydrodiazepinoquinolines carrying a cyclic radical

ABSTRACT

The present invention relates to tricyclic hexahydrodiazepinoquinolines carrying a cyclic substituent, to a method for producing them, to a pharmaceutical composition containing such compounds, to their use as modulators, especially agonists or partial agonists, of the 5-HT 2C  receptor, their use for preparing a medicament for the prevention or treatment of conditions and disorders which respond to the modulation of 5-HT 2C  receptor, to a method for preventing or treating conditions and disorders which respond to the modulation of 5-HT 2C  receptor, and processes for preparing such compounds and compositions.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This claims priority to U.S. Provisional Patent Application No.61/953,424, filed on Mar. 14, 2014, the entire contents of which arefully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to tricyclic hexahydrodiazepinoquinolinescarrying a cyclic substituent, to a method for producing them, to apharmaceutical composition containing such compounds, to their use asmodulators, especially agonists or partial agonists, of the 5-HT_(2C)receptor, their use for preparing a medicament for the prevention ortreatment of conditions and disorders which respond to the modulation of5-HT_(2C) receptor, to a method for preventing or treating conditionsand disorders which respond to the modulation of 5-HT_(2C) receptor, andprocesses for preparing such compounds and compositions.

BACKGROUND OF THE INVENTION

Diseases, disorders and conditions where 5-HT_(2C) modulation is desiredare for example depression, anxiety, schizophrenia, bipolar disorder,obsessive compulsive disorder, migraine, pain, epilepsy, substanceabuse, eating disorders, obesity, diabetes, erectile dysfunction andothers.

Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter andlocal hormone, is formed by the hydroxylation and decarboxylation oftryptophan. The greatest concentration is found in the enterochromaffincells of the gastrointestinal tract, the remainder being predominantlypresent in platelets and in the Central Nervous System (CNS). 5-HT isimplicated in a vast array of physiological and pathophysiologicalpathways. In the periphery, it contracts a number of smooth muscles andinduces endothelium-dependent vasodilation. In the CNS, it is believedto be involved in a wide range of functions, including the control ofappetite, mood, anxiety, hallucinations, sleep, vomiting and painperception.

Neurons that secrete 5-HT are termed serotonergic. The function of 5-HTis exerted upon its interaction with specific (serotonergic) neurons.Seven types of 5-HT receptors have been identified: 5-HT₁ (with subtypes5-HT_(1A), 5-HT_(1B), 5-HT_(1D), 5-HT_(1E) and 5-HT_(1F)), 5-HT₂ (withsubtypes 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C)), 5-HT₃, 5-HT₄, 5-HT₅ (withsubtypes 5-HT_(5A) and 5-HT_(5B)), 5-HT₆ and 5-HT₇. Most of thesereceptors are coupled to G-proteins that affect the activities ofadenylate cyclase or phospholipase Cγ.

Alterations in the activity of multiple neurotransmitter receptorsystems (dopamine, serotonin, glutamate, GABA, acetylcholine) have beenimplicated in the manifestation of the symptoms of schizophrenia. Themost widely accepted “Dopamine Hypothesis of Schizophrenia” in itssimplest form states that the positive symptoms of this pathology relateto a functional hyperactivity of the mesolimbic dopaminergic system,while the negative and cognitive aspects can be traced to a functionalhypoactivity of the mesocortical dopaminergic projections. Atypicalantipsychotics block the mesolimbic dopaminergic neurotransmission,thereby controlling positive symptoms, with little or no effect on thenigrostriatal system, leading to less induction of extrapyramidal sideeffects (EPS).

Primary negative and cognitive symptoms of schizophrenia reflect adysfunction of the frontal cortex (“hypofrontality”), which is thoughtto be induced by a decreased tone in the mesocortical dopaminergicprojection field [Davis K L, Kahn R S, Ko G and Davidson M (1991).Dopamine in schizophrenia: a review and re-conceptualization. Am JPsychiatry 148: 1474-86. Weinberger D R and Berman K F (1996).Prefrontal function in schizophrenia: confounds and controversies.Philos Trans R Soc Lond B Biol Sci 351: 1495-503]. Agents thatselectively enhance dopamine levels in the cortex have the potential toaddress the negative symptoms of this disorder. Atypical antipsychoticslack robust efficacy against negative and cognitive components of theschizophrenic syndrome.

The schizophrenic symptomatology is further complicated by theoccurrence of drug-induced so-called secondary negative symptoms andcognitive impairment, which are difficult to distinguish from primarynegative and cognitive symptoms [Remington G and Kapur S (2000).Atypical antipsychotics: are some more atypical than others?Psychopharmacol 148: 3-15]. The occurrence of secondary negativesymptoms not only limits therapeutic efficacy but also, together withthese side effects, negatively affects patient compliance.

It may thus be hypothesized that a novel mechanistic approach thatblocks dopaminergic neurotransmission in the limbic system but does notaffect the striatal and pituitary projection fields, and stimulatesfrontocortical projection fields, would provide an efficacious treatmentfor all parts of the schizophrenic pathology, including its positive,negative and cognitive symptoms. Moreover, a selective compound that issubstantially free of the ancillary pharmacology that characterizescurrent agents would be expected to avoid a variety of off-target sideeffects that plague current treatments such as extrapyramidal sideeffects (EPS) and weight gain.

The 5-HT_(2C) receptor, previously named 5-HT1C, is a G-protein-coupledreceptor, which couples to multiple cellular effector systems includingthe phospholipase C, A and D pathways. It is found primarily in thebrain and its distribution is particularly high in the plexuschoroideus, where it is assumed to control cerebrospinal fluidproduction [Kaufman M J, Hirata F (1996) Cyclic GMP inhibitsphosphoinositide turnover in choroid plexus: evidence for interactionsbetween second messengers concurrently triggered by 5-HT_(2C) receptors.Neurosci Lett 206:153-156]. Very high levels were also found in theretrosplenial, piriform and entorhinal cortex, anterior olfactorynucleus, lateral septal nucleus, subthalamic nucleus, amygdala,subiculum and ventral part of CA3, lateral habenula, substantia nigrapars compacta, several brainstem nuclei and the whole grey matter of thespinal cord [Pompeiano M, Palacios J M, Mengod G (1994). Distribution ofthe serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT_(2A)and 5-HT_(2C) receptors. Brain Res Mol Brain Res 23:163-178]. Acomparison of the distribution of 5-HT_(2C) mRNA with that of 5-HT_(2C)protein in monkey and human brains has revealed both pre- andpostsynaptic localization [Lopez-Gimenez J F, Mengod G, Palacios J M,Vilaro M T (2001) Regional distribution and cellular localization of5-HT_(2C) receptor mRNA in monkey brain: comparison with [³H]mesulerginebinding sites and choline acetyltransferase mRNA. Synapse 42:12-26].

It is anticipated that modulation of the 5-HT_(2C) receptor will improvedisorders such as depression, anxiety, schizophrenia, cognitive deficitsof schizophrenia, obsessive compulsive disorder, bipolar disorder,neuropsychiatric symptoms in Parkinson′ disease, in Alzheimer's diseaseor Lewy Body dementia, migraine, epilepsy, substance abuse, eatingdisorders, obesity, diabetes, sexual dysfunction/erectile dysfunction,sleep disorders, psoriasis, Parkinson's disease, pain conditions anddisorders, and spinal cord injury, smoking cessation, ocularhypertension and Alzheimer's disease. Modulators of the 5-HT_(2C)receptor are also shown to be useful in the modulation of bladderfunction, including the prevention or treatment of urinary incontinence.

Compounds with a structure similar to the compounds of the presentinvention have been described in WO 2014/041131 and WO 03/091250.

There is an ongoing need for providing compounds having high affinityand in particular also high selectivity for the 5-HT_(2C) receptor. Inparticular the compounds should have low affinity to adrenergicreceptors, such as the α₁-adrenergic receptor, histamine receptors, suchas the H₁-receptor, and dopaminergic receptors, such as the D₂-receptor,in order to avoid or reduce side effects associated with modulation ofthese receptors, such as postural hypotension, reflex tachycardia,potentiation of the antihypertensive effect of prazosin, terazosin,doxazosin and labetalol or dizziness associated with the blockade of theα₁-adrenergic receptor, weight gain, sedation, drowsiness orpotentiation of central depressant drugs associated with the blockade ofthe H₁-receptor, or extrapyramidal movement disorder, such as dystonia,parkinsonism, akathisia, tardive dyskinesia or rabbit syndrome, orendocrine effects, such as prolactin elevation (galactorrhea,gynecomastia, mentstrual changes, sexual dysfunction in males),associated with the blockade of the D₂-receptor, and even more importantno induction of weight gain in combination with severe metabolicdysfunction found for marketed antipsychotic drugs.

It is moreover desirable that the compounds have low affinity oralternatively an antagonistic effect to/on other serotonergic receptors,especially the 5-HT_(2A) and/or 5-HT_(2B) receptors, in order to avoidor reduce side effects associated with modulation of these receptors,such as changes (thickening) of the heart tissue associated with agonismat the 5-HT_(2B) receptor, and psychotomimetic effect induced by agonismat the 5-HT_(2A) receptor. Ideally they should show an agonistic actionon the 5-HT_(2C) receptor, an antagonistic action on the 5-HT_(2A)receptor or alternatively no affinity to the 5-HT_(2A) receptor and noaffinity to the 5-HT_(2B) receptor or alternatively an antagonisticaction on the 5-HT_(2B) receptor. Even more ideally the compounds shoulddisplay an agonistic action on the 5-HT_(2C) receptor in combinationwith an antagonistic action on the 5-HT_(2A) receptor and no affinity tothe 5-HT_(2B) receptor.

Besides the affinity and selectivity for the 5-HT_(2C) receptor, furtherproperties may be advantageous for the treatment and/or prophylaxis of5-HT_(2C)-related disorders, such as, for example:

1.) the metabolic stability, for example determined from the half-lives,measured in vitro, in liver microsomes from various species (e.g. rat orhuman);

2.) no or only low inhibition of cytochrome P450 (CYP) enzymes:cytochrome P450 (CYP) is the name for a superfamily of heme proteinshaving enzymatic activity (oxidase). They are also particularlyimportant for the degradation (metabolism) of foreign substances such asdrugs or xenobiotics in mammalian organisms. The principalrepresentatives of the types and subtypes of CYP in the human body are:CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g.grapefruit juice, cimetidine, erythromycin) are used at the same time asmedicinal substances which are degraded by this enzyme system and thuscompete for the same binding site on the enzyme, the degradation thereofmay be slowed down and thus effects and side effects of the administeredmedicinal substance may be undesirably enhanced;

3.) a suitable solubility in water (in mg/mL);

4.) suitable pharmacokinetics (time course of the concentration of thecompound of the invention in plasma or in tissue, for example brain).The pharmacokinetics can be described by the following parameters:half-life (in h), volume of distribution (in l·kg-l), plasma clearance(in l·h-l·kg-l), AUC (area under the curve, area under theconcentration-time curve, in ng·h·l-l), oral bioavailability (thedose-normalized ratio of AUC after oral administration and AUC afterintravenous administration), the so-called brain-plasma ratio (the ratioof AUC in brain tissue and AUC in plasma);

5.) no or only low blockade of the hERG channel: compounds which blockthe hERG channel may cause a prolongation of the QT interval and thuslead to serious disturbances of cardiac rhythm (for example so-called“torsade de pointes”). The potential of compounds to block the hERGchannel can be determined by means of the displacement assay withradiolabelled dofetilide which is described in the literature (G. J.Diaz et al., Journal of Pharmacological and Toxicological Methods, 50(2004), 187 199). A smaller IC50 in this dofetilide assay means agreater probability of potent hERG blockade. In addition, the blockadeof the hERG channel can be measured by electrophysiological experimentson cells which have been transfected with the hERG channel, by so-calledwhole-cell patch clamping (G. J. Diaz et al., Journal of Pharmacologicaland Toxicological Methods, 50 (2004), 187-199).

It was an object of the present invention to provide compounds for thetreatment or prophylaxis of various 5-HT_(2C)-related diseases. Thecompounds were intended to have a high affinity to the 5-HT_(2C)receptor and be potent and efficacious 5-HT_(2C) agonists. In addition,the compounds of the invention were intended to have one or more of theaforementioned advantages, namely low affinity on other serotonergicreceptors, and especially the lack of potent agonistic effect(antagonism preferred) on the 5-HT_(2A) and/or 5-HT_(2B) receptors, andadditionally one or more of those advantages mentioned under 1.) to 5.).

The present invention provides compounds which have an affinity for the5-HT_(2C), thus allowing the treatment of disorders related to oraffected by the 5-HT_(2C) receptor.

SUMMARY OF THE INVENTION

The present invention relates to tricyclic hexahydrodiazepinoquinolinescarrying a cyclic substituent, to a method for producing them, tocompositions comprising such compounds, their use as modulators,especially agonists or partial agonists, of the 5-HT_(2C) receptor,their use for preparing a medicament for the prevention or treatment ofconditions and disorders which respond to the modulation of 5-HT_(2C)receptor, to a method for preventing or treating conditions anddisorders which respond to the modulation of 5-HT_(2C) receptor, andprocesses for preparing such compounds and compositions.

In one aspect, the present invention relates to compounds of the formula(I):

wherein

-   R¹ is selected from the group consisting of hydrogen, cyano,    C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl and a    3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4    heteroatoms or heteroatom groups independently selected from N, O,    S, NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups    as ring members, where the cyclic moieties in the three    last-mentioned radicals may be substituted with one or more    substituents R¹⁰;-   each R² is independently selected from the group consisting of    cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,    C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated    C₁-C₆-alkoxy-C₁-C₄-alkyl, —CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl,    phenyl-C₁-C₂-alkyl, and a 3-, 4-, 5-, 6-, 7- or 8-membered    saturated, partially unsaturated or maximally unsaturated ring    containing 1, 2, 3 or 4 heteroatoms or heteroatom groups    independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as    ring members, where the cyclic moieties in the six last-mentioned    radicals may be substituted with one or more substituents R¹⁰; or    -   two radicals R² bound to the same carbon atom, together with the        carbon atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or        8-membered saturated, partially unsaturated or maximally        unsaturated ring (i.e. a spiro-bound ring), where the ring may        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        R¹⁰;-   R^(3a) and R^(3b), independently of each other, are selected from    the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl,    fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,    fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl,    —CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-,    4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹⁰;-   R^(4a) and R^(4b), independently of each other, are selected from    the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl,    fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,    fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl,    —CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-,    4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹⁰; or    -   R^(4a) and R^(4b) form together a group ═O or ═S; or    -   R^(4a) and R^(4b), together with the carbon atom they are bound        to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring (i.e. a spiro-bound        ring), where the ring may contain 1, 2, 3 or 4 heteroatoms or        heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O        and C═S as ring members, and where the ring may be substituted        with one or more substituents R¹⁰;-   R^(5a) and R^(5b), independently of each other, are selected from    the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl,    C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl,    C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated    C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy,    C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated    C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(11a)R^(11b), CH₂NR^(11a)R^(11b),    —NR^(11a)C(O)R⁹, —C(═O)R⁹, SO₂NR^(11a)R^(11b), C₁-C₆    alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-,    5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹⁰; where    -   R^(5a) and R^(5b) are not simultaneously hydroxyl; or    -   R^(5a) and R^(5b), together with the carbon atom they are bound        to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring (i.e. a spiro-bound        ring), where the ring may contain 1, 2, 3 or 4 heteroatoms or        heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O        and C═S as ring members, and where the ring may be substituted        with one or more substituents R¹⁰;-   R⁶ is a cyclic radical selected from the group consisting of    C₃-C₆-cycloalkyl which may carry one or more radicals R⁸; and a 3-,    4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4    heteroatoms or heteroatom groups independently selected from N, O,    S, NO, SO and SO₂, and optionally also 1 or 2 groups C═O and/or C═S,    as ring members, where the heterocyclic ring may be substituted with    one or more substituents R¹⁰;-   each R⁷ is independently selected from the group consisting of    halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl,    fluorinated C₃-C₈-cycloalkenyl, C₁-C₆-alkoxy, fluorinated    C₁-C₆-alkoxy, C₁-C₆ alkoxy C₁-C₄ alkyl, fluorinated    C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy,    C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated    C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b),    —NR^(11a)C(O)R⁹, —C(O)R⁹, SO₂NR^(11a)R^(11b), C6-alkylcarbonyloxy,    fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl,    phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or    8-membered saturated, partially unsaturated or maximally unsaturated    ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups    independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as    ring members, where the cyclic moieties in the six last-mentioned    radicals may be substituted with one or more substituents R¹⁰; or    -   two radicals R⁷ bound on neighboring carbon atoms, together with        the carbon atoms they are bound to, form a 3-, 4-, 5-, 6-, 7- or        8-membered partially unsaturated or maximally unsaturated ring,        where the ring may contain 1, 2, 3 or 4 heteroatoms or        heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O        and C═S as ring members, and where the ring may be substituted        with one or more substituents R¹⁰;-   each R⁸ is independently selected from the group consisting of    halogen, cyano, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,    C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated    C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated    C₁-C₆-alkoxy-C₁-C₄-alkyl, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b),    phenyl, phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-,    7- or 8-membered saturated, partially unsaturated or maximally    unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom    groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S    as ring members, where the cyclic moieties in the five    last-mentioned radicals may be substituted with one or more    substituents R¹⁰;    -   or two radicals R⁸ bound to the same carbon atom may form        together a group ═O or ═S;-   each R⁹ is independently selected from the group consisting of    hydrogen, cyano, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,    C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated    C₁-C₆-alkoxy, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b), phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or    8-membered saturated, partially unsaturated or maximally unsaturated    ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups    independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as    ring members, where the cyclic moieties in the five last-mentioned    radicals may be substituted with one or more substituents R¹⁰;-   each R¹⁰ is independently selected from the group consisting of    halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated    C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy,    C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated    C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —COOH, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b),    C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl,    C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl,    SO₂NR^(11a)R^(11b), C₁-C₆-alkylcarbonyloxy and fluorinated    C₁-C₆-alkylcarbonyloxy;    -   or two radicals R¹⁰, together with the atom(s) they are bound        to, form a saturated, partially unsaturated or maximally        unsaturated 3-, 4-, 5-, 6- or 7-membered carbocyclic or        heterocyclic ring, where the heterocyclic ring contains 1, 2 or        3 heteroatoms or heteroatom groups independently selected from        N, O, S, NO, SO, SO₂, C═O and C═S as ring members;-   R^(11a) and R^(11b), independently of each other and independently    of each occurrence, are selected from the group consisting of    hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated    C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,    fluorinated C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinated    C₁-C₆-alkoxycarbonyl, phenyl and benzyl, where the phenyl moieties    in the two last-mentioned radicals may carry 1, 2 or 3 substituents    selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; or,    -   if R^(11a) and R^(11b) are bound to the same nitrogen atom,        together with this nitrogen atom may form a 3-, 4-, 5-, 6-, 7-        or 8-membered saturated, partially unsaturated or maximally        unsaturated heterocyclic ring, where the ring may further        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated        C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy;        a is 0, 1 or 2; and        b is 0, 1, 2 or 3;        or an N-oxide, a tautomeric form, a stereoisomer or a        pharmaceutically acceptable salt thereof

In another aspect, the invention relates to a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof formula I or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof, in combination with at leastone pharmaceutically acceptable carrier and/or auxiliary substance.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for use as a medicament.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for the treatment of disorders which responds tothe modulation of the 5-HT_(2C) receptor.

In yet another aspect, the invention relates to the use of a compound offormula I or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders which respond to themodulation of the 5-HT_(2C) receptor.

In yet another aspect, the invention relates to the use of a compound offormula I or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders selected from the groupconsisting of damage of the central nervous system, disorders of thecentral nervous system, eating disorders, ocular hypertension,cardiovascular disorders, gastrointestinal disorders and diabetes, andespecially from the group consisting of bipolar disorder, depression,atypical depression, mood episodes, adjustment disorders, anxiety, panicdisorders, post-traumatic syndrome, psychoses, schizophrenia, cognitivedeficits of schizophrenia, memory loss, dementia of aging, Alzheimer'sdisease, neuropsychiatric symptoms in Alzheimer's disease (e.g.aggression), behavioral disorders associated with dementia, socialphobia, mental disorders in childhood, attention deficit hyperactivitydisorder, organic mental disorders, autism, mutism, disruptive behaviordisorder, impulse control disorder, borderline personality disorder,obsessive compulsive disorder, migraine and other conditions associatedwith cephalic pain or other pain, raised intracranial pressure, seizuredisorders, epilepsy, substance use disorders, alcohol abuse, cocaineabuse, tobacco abuse, smoking cessation, sexual dysfunction/erectiledysfunction in males, sexual dysfunction in females, premenstrualsyndrome, late luteal phase syndrome, chronic fatigue syndrome, sleepdisorders, sleep apnoea, chronic fatigue syndrome, psoriasis,Parkinson's disease, neuropsychiatric symptoms in Parkinson's disease(e.g. aggression), Lewy Body dementia, neuropsychiatric symptoms in LewyBody dementia (e.g. aggression), spinal cord injury, trauma, stroke,pain, bladder dysfunction/urinary incontinence, encephalitis,meningitis, eating disorders, obesity, bulimia, weight loss, anorexianervosa, ocular hypertension, cardiovascular disorders, gastrointestinaldisorders, diabetes insipidus, diabetes mellitus, type I diabetes, typeII diabetes, type III diabetes, diabetes secondary to pancreaticdiseases, diabetes related to steroid use, diabetes complications,hyperglycemia and insulin resistance.

In yet another aspect, the invention relates to a method for treatingdisorders which respond to the modulation of the 5-HT_(2C) receptor,which method comprises administering to a subject in need thereof atleast one compound of formula I or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof.

In yet another aspect, the invention relates to a method for treatingdisorders selected from the group consisting of damage of the centralnervous system, disorders of the central nervous system, eatingdisorders, ocular hypertension, cardiovascular disorders,gastrointestinal disorders and diabetes, and especially from the groupconsisting of bipolar disorder, depression, atypical depression, moodepisodes, adjustment disorders, anxiety, panic disorders, post-traumaticsyndrome, psychoses, schizophrenia, cognitive deficits of schizophrenia,memory loss, dementia of aging, Alzheimer's disease, neuropsychiatricsymptoms in Alzheimer's disease (e.g. aggression), behavioral disordersassociated with dementia, social phobia, mental disorders in childhood,attention deficit hyperactivity disorder, organic mental disorders,autism, mutism, disruptive behavior disorder, impulse control disorder,borderline personality disorder, obsessive compulsive disorder, migraineand other conditions associated with cephalic pain or other pain, raisedintracranial pressure, seizure disorders, epilepsy, substance usedisorders, alcohol abuse, cocaine abuse, tobacco abuse, smokingcessation, sexual dysfunction/erectile dysfunction in males, sexualdysfunction in females, premenstrual syndrome, late luteal phasesyndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea,chronic fatigue syndrome, psoriasis, Parkinson's disease,neuropsychiatric symptoms in Parkinson's disease (e.g. aggression), LewyBody dementia, neuropsychiatric symptoms in Lewy Body dementia (e.g.aggression), spinal cord injury, trauma, stroke, pain, bladderdysfunction/urinary incontinence, encephalitis, meningitis, eatingdisorders, obesity, bulimia, weight loss, anorexia nervosa, ocularhypertension, cardiovascular disorders, gastrointestinal disorders,diabetes insipidus, diabetes mellitus, type I diabetes, type IIdiabetes, type III diabetes, diabetes secondary to pancreatic diseases,diabetes related to steroid use, diabetes complications, hyperglycemiaand insulin resistance, which method comprises administering to asubject in need thereof at least one compound of formula I or anN-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION

The compounds of the formula I may exist in different spatialarrangements. For example, if the compounds possess one or more centersof asymmetry, polysubstituted rings or double bonds, or as differenttautomers, the present invention contemplates the possible use ofenantiomeric mixtures, in particular racemates, diastereomeric mixturesand tautomeric mixtures, such as the respective essentially pureenantiomers, diastereomers and tautomers of the compounds of formula Iand/or their salts.

It is likewise possible to use physiologically tolerated salts of thecompounds of the formula I, especially acid addition salts withphysiologically tolerated acids. Examples of suitable physiologicallytolerated organic and inorganic acids are hydrochloric acid, hydrobromicacid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid,C₁-C₄-alkylsulfonic acids, such as methanesulfonic acid, aromaticsulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid,oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid,adipic acid and benzoic acid. Other utilizable acids are described inFortschritte der Arzneimittelforschung [Advances in drug research],Volume 10, pages 224 et seq., Birkhäauser Verlag, Basel and Stuttgart,1966.

The compounds of formula I may also be present in the form of tautomers.In one aspect, tautomery may be present in compounds I wherein R^(4a)and R^(4b) form together a group ═O and R^(5a) or R^(5b) is H. Forexample, the compounds of formula I may have the following tautomericformulae:

In another aspect, tautomery may be present in compounds I containingrings which have one or more C═O groups as ring members which areneighbored to a CH₂ group.

The organic moieties mentioned in the above definitions of the variablesare, like the term halogen, collective terms for individual listings ofthe individual group members. The prefix C_(n)-C_(m) indicates in eachcase the possible number of carbon atoms in the group.

The term “halogen” denotes in each case fluorine, bromine, chlorine oriodine. In one aspect, the halogen may be fluorine, chlorine or bromine.

The term “alkyl” as used herein and in the alkyl moieties of alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyland the like refers to saturated straight-chain or branched hydrocarbonradicals having 1 to 2 (“C₁-C₂-alkyl”), 1 to 3 (“C₁-C₃-alkyl”), 1 to 4(“C₁-C₄-alkyl”) or 1 to 6 (“C₁-C₆-alkyl”) carbon atoms. C₁-C₂-Alkyl ismethyl or ethyl. C₁-C₃-Alkyl is additionally propyl and isopropyl.C₁-C₄-Alkyl is additionally butyl, 1-methylpropyl (sec-butyl),2-methylpropyl (isobutyl) or 1,1-dimethylethyl (tert-butyl). C₁-C₆-Alkylis additionally also, for example, pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or1-ethyl-2-methylpropyl.

The term “fluorinated alkyl” as used herein refers to straight-chain orbranched alkyl groups having 1 to 2 (“fluorinated C₁-C₂-alkyl”), 1 to 3(“fluorinated C₁-C₃-alkyl”), 1 to 4 (“fluorinated C₁-C₄-alkyl”) or 1 to6 (“fluorinated C₁-C₆-alkyl”) carbon atoms (as mentioned above), wheresome or all of the hydrogen atoms in these groups are replaced byfluorine atoms. Fluorinated C₁-C₂-alkyl is an alkyl group having 1 or 2carbon atoms (as mentioned above), where at least one of the hydrogenatoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replacedby fluorine atoms, such as difluoromethyl, trifluoromethyl,1-fluoroethyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl.Fluorinated C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms (as mentioned above), where at least one ofthe hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groupsare replaced by fluorine atoms. Examples are, apart those listed abovefor C₁-C₂-fluoroalkyl, 1-fluoropropyl, (R)-1-fluoropropyl,(S)-1-fluoropropyl, 2-fluoropropyl, (R)-2-fluoropropyl,(S)-2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl,2,2-difluoropropyl, 1,2-difluoropropyl, 2,3-difluoropropyl,1,3-difluoropropyl, 3,3-difluoropropyl, 1,1,2-trifluoropropyl,1,2,2-trifluoropropyl, 1,2,3-trifluoropropyl, 2,2,3-trifluoropropyl,3,3,3-trifluoropropyl, 1,1,1-trifluoroprop-2-yl, 2-fluoro-1-methylethyl,(R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl,2,2-difluoro-1-methylethyl, (R)-2,2-difluoro-1-methylethyl,(S)-2,2-difluoro-1-methylethyl, 1,2-difluoro-1-methylethyl,(R)-1,2-difluoro-1-methylethyl, (S)-1,2-difluoro-1-methylethyl,2,2,2-trifluoro-1-methylethyl, (R)-2,2,2-trifluoro-1-methylethyl,(S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyl)ethyl,1-(difluoromethyl)-2,2-difluoroethyl,1-(trifluoromethyl)-2,2,2-trifluoroethyl,1-(trifluoromethyl)-1,2,2,2-tetrafluoroethyl, 1-fluorobutyl,(R)-1-fluorobutyl, (S)-1-fluorobutyl, 2-fluorobutyl, (R)-2-fluorobutyl,(S)-2-fluorobutyl, 3-fluorobutyl, (R)-3-fluorobutyl, (S)-3-fluorobutyl,4-fluorobutyl, 1,1-difluorobutyl, 2,2-difluorobutyl, 3,3-difluorobutyl,4,4-difluorobutyl, 4,4,4-trifluorobutyl and the like. FluorinatedC₁-C₆-alkyl is a straight-chain or branched alkyl group having 1 to 6carbon atoms (as mentioned above), where at least one of the hydrogenatoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replacedby fluorine atoms. Additionally examples include for C₁-C₄-fluoroalkyl,1-fluoropentyl, (R)-1-fluoropentyl, (S)-1-fluoropentyl, 2-fluoropentyl,(R)-2-fluoropentyl, (S)-2-fluoropentyl, 3-fluoropentyl,(R)-3-fluoropentyl, (S)-3-fluoropentyl, 4-fluoropentyl,(R)-4-fluoropentyl, (S)-4-fluoropentyl, 5-fluoropentyl,(R)-5-fluoropentyl, (S)-5-fluoropentyl, 1-fluorohexyl,(R)-1-fluorohexyl, (S)-1-fluorohexyl, 2-fluorohexyl, (R)-2-fluorohexyl,(S)-2-fluorohexyl, 3-fluorohexyl, (R)-3-fluorohexyl, (S)-3-fluorohexyl,4-fluorohexyl, (R)-4-fluorohexyl, (S)-4-fluorohexyl, 5-fluorohexyl,(R)-5-fluorohexyl, (S)-5-fluorohexyl, 6-fluorohexyl, (R)-6-fluorohexyl,(S)-6-fluorohexyl, and the like.

The term “alkenyl” as used herein refers to monounsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“C₂-C₃-alkenyl”), 2 to 4 (“C₂-C₄-alkenyl”) or 2 to 6 (“C₂-C₆-alkenyl”)carbon atoms and a double bond in any position, such as C₂-C₃-alkenyl,such as ethenyl, 1-propenyl, 2-propenyl or 1-methylethenyl;C₂-C₄-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl; andC₂-C₆-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl,2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl,3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl,1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl,2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl,3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl,1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl,1-ethyl-2-methyl-2-propenyl and the like.

The term “fluorinated alkenyl” as used herein refers to unsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“fluorinated C₂-C₃-alkenyl”), 2 to 4 (“fluorinated C₂-C₄-alkenyl”) or 2to 6 (“fluorinated C₂-C₆-alkenyl”) carbon atoms and a double bond in anyposition (as mentioned above), where some or all of the hydrogen atomsin these groups are replaced by fluorine atoms, such as, fluorovinyl,fluoroallyl and the like.

The term “alkynyl” as used herein refers to straight-chain or branchedhydrocarbon groups having 2 to 3 (“C₂-C₃-alkynyl”), 2 to 4(“C₂-C₄-alkynyl”) or 2 to 6 (“C2-C6-alkynyl”) carbon atoms and one ortwo triple bonds in any position, such as C₂-C₃-alkynyl, such asethynyl, 1-propynyl or 2-propynyl; C₂-C₄-alkynyl, such as ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl and the like, and C₂-C₆-alkynyl, such as ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl,3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl,1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl,1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl andthe like.

The term “fluorinated alkynyl” as used herein refers to unsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“fluorinated C₂-C₃-alkynyl”), 3 to 4 (“fluorinated C₃-C₄-alkynyl”) or 2to 6 (“fluorinated C₂-C₆-alkynyl”) carbon atoms and one or two triplebonds in any position (as mentioned above), where some or all of thehydrogen atoms in these groups are replaced by fluorine atoms.

The term “cycloalkyl” as used herein refers to monocyclic saturatedhydrocarbon radicals having 3 to 8 (“C₃-C₈-cycloalkyl”), in particular 3to 6 carbon atoms (“C₃-C₆-cycloalkyl”) or 3 to 5 carbon atoms(“C₃-C₅-cycloalkyl”) or 3 or 4 carbon atoms (“C₃-C₄-cycloalkyl”).Examples for C₃-C₄-cycloalkyl are cyclopropyl and cyclobutyl. Examplesof C₃-C₅-cycloalkyl are cyclopropyl, cyclobutyl and cyclopentyl.Examples of C₃-C₆-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. Examples of C₃-C₈-cycloalkyl are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term “fluorinated cycloalkyl” as used herein refers to monocyclicsaturated hydrocarbon groups having 3 to 8 (“C₃-C₈-halocycloalkyl”) orpreferably 3 to 6 (“C₃-C₆-halocycloalkyl”) or 3 to 5(“C₃-C₅-halocycloalkyl”) carbon ring members (as mentioned above) inwhich some or all of the hydrogen atoms are replaced by fluorine atoms.Examples include 1-fluorocyclopropyl, 2-fluorocyclopropyl, (S)- and(R)-2,2-difluorocyclopropyl, 1,2-difluorocyclopropyl,2,3-difluorocyclopropyl, pentafluorocyclopropyl, 1-fluorocyclobutyl,2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl,3,3-difluorocyclobutyl, 1,2-difluorocyclobutyl, 1,3-difluorocyclobutyl,2,3-difluorocyclobutyl, 2,4-difluorocyclobutyl,1,2,2-trifluorocyclobutyl, 1-fluorocycloheptyl, 2-fluorocycloheptyl,3-fluorocycloheptyl, 4-fluorocycloheptyl, 1,2-difluorocycloheptyl,1,3-difluorocycloheptyl, 1,4-difluorocycloheptyl,2,2-difluorocycloheptyl, 2,3-difluorocycloheptyl,2,4-difluorocycloheptyl, 2,5-difluorocycloheptyl,2,6-difluorocycloheptyl, 2,7-difluorocycloheptyl,3,3-difluorocycloheptyl, 3,4-difluorocycloheptyl,3,5-difluorocycloheptyl, 3,6-difluorocycloheptyl,4,4-difluorocycloheptyl, 4,5-difluorocycloheptyl, and the like.

The term “cycloalkenyl” as used herein refers to monocyclic partiallyunsaturated, non-aromatic hydrocarbon radicals having 3 to 8(“C₃-C₈-cycloalkenyl”), in particular 5 to 7 carbon atoms(“C₅-C₇-cycloalkenyl”) or 5 or 6 carbon atoms (“C₅-C₆-cycloalkenyl”) andone or more non-cumulative, preferably one, C—C double bonds in thering. Examples for C₅-C₆-cycloalkenyl are cyclopent-1-en-1-yl,cyclopent-1-en-3-yl, cyclopent-1-en-4-yl, cyclopenta-1,3-dien-1-yl,cyclopenta-1,3-dien-2-yl, cyclopenta-1,3-dien-5-yl, cyclohex-1-en-1-yl,cyclohex-1-en-3-yl, cyclohex-1-en-4-yl, cyclohexa-1,3-dien-1-yl,cyclohexa-1,3-dien-2-yl, cyclohexa-1,3-dien-5-yl,cyclohexa-1,4-dien-1-yl and cyclohexa-1,4-dien-3-yl. Examples ofC₅-C₇-cycloalkenyl are, apart those mentioned above, include forC₅-C₆-cycloalkenyl, cyclohept-1-en-1-yl, cyclohept-1-en-3-yl,cyclohept-1-en-4-yl, cyclohept-1-en-5-yl, cyclohepta-1,3-dien-1-yl,cyclohepta-1,3-dien-2-yl, cyclohepta-1,3-dien-5-yl,cyclohepta-1,3-dien-6-yl, cyclohepta-1,4-dien-1-yl,cyclohepta-1,4-dien-2-yl, cyclohepta-1,4-dien-3-yl andcyclohepta-1,4-dien-6-yl. Examples of C₃-C₈-cycloalkenyl are, apartthose mentioned above for C₅-C₆-cycloalkenyl, cycloprop-1-en-1-yl,cycloprop-1-en-3-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclooct-1-en-1-yl, cyclooct-1-en-3-yl, cyclooct-1-en-4-yl,cyclooct-1-en-5-yl, cycloocta-1,3-dien-1-yl, cycloocta-1,3-dien-2-yl,cycloocta-1,3-dien-5-yl, cycloocta-1,3-dien-6-yl,cycloocta-1,4-dien-1-yl, cycloocta-1,4-dien-2-yl,cycloocta-1,4-dien-3-yl, cycloocta-1,4-dien-6-yl,cycloocta-1,4-dien-7-yl, cycloocta-1,5-dien-1-yl, andcycloocta-1,5-dien-3-yl.

The term “fluorinated cycloalkenyl” as used herein refers to monocyclicpartially unsaturated, non-aromatic hydrocarbon radicals having 3 to 8(“fluorinated C₃-C₈-cycloalkenyl”), in particular 5 to 7 carbon atoms(“fluorinated C₅-C₇-cycloalkenyl”) or 5 or 6 carbon atoms (“fluorinatedC₅-C₆-cycloalkenyl”) and one or more non-cumulative, preferably one, C—Cdouble bonds in the ring and in which some or all of the hydrogen atomsare replaced by fluorine atoms.

The term “cycloalkyl-C₁-C₄-alkyl” refers to a C₃-C₈-cycloalkyl group(“C₃-C₈-cycloalkyl-C₁-C₄-alkyl”), preferably a C₃-C₆-cycloalkyl group(“C₃-C₆-cycloalkyl-C₁-C₄-alkyl”) as defined above which is bound to theremainder of the molecule via a C₁-C₄-alkyl group, as defined above. Theterm “cycloalkyl-C₁-C₂-alkyl” refers to a C₃-C₈-cycloalkyl group(“C₃-C₈-cycloalkyl-C₁-C₂-alkyl”), preferably a C₃-C₆-cycloalkyl group(“C₃-C₆-cycloalkyl-C₁-C₂-alkyl”) as defined above which is bound to theremainder of the molecule via a C₁-C₂-alkyl group, as defined above.Examples for C₃-C₆-cycloalkyl-C₁-C₂-alkyl are cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl,cyclopentylethyl, cyclohexylmethyl and cyclohexylethyl. Examples forC₃-C₆-cycloalkyl-C₁-C₄-alkyl, apart those mentioned forC₃-C₆-cycloalkyl-C₁-C₂-alkyl, are cyclopropylpropyl, cyclopropylbutyl,cyclobutylpropyl, cyclobutylbutyl, cyclopentylpropyl, cyclopentylbutyl,cyclohexylpropyl and cyclohexylbutyl. Examples forC₃-C₈-cycloalkyl-C₁-C₂-alkyl, apart those mentioned forC₃-C₆-cycloalkyl-C₁-C₂-alkyl, are cycloheptylmethyl, cycloheptylethyl,cyclooctylmethyl and cyclooctylethyl. Examples forC₃-C₈-cycloalkyl-C₁-C₄-alkyl, apart those mentioned forC₃-C₈-cycloalkyl-C₁-C₂-alkyl, are cycloheptylpropyl, cycloheptylbutyl,cyclooctylpropyl and cyclooctylbutyl.

The term “fluorinated cycloalkyl-C₁-C₄-alkyl” refers to a fluorinatedC₃-C₈-cycloalkyl group (“fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl”),preferably a fluorinated C3-C6-cycloalkyl group (“fluorinatedC₃-C₆-cycloalkyl-C₁-C₄-alkyl”) as defined above which is bound to theremainder of the molecule via a C₁-C₄-alkyl group, as defined above. Theterm “fluorinated cycloalkyl-C₁-C₂-alkyl” refers to a fluorinatedC₃-C₈-cycloalkyl group (“fluorinated C₃-C₈-cycloalkyl-C₁-C₂-alkyl”),preferably a fluorinated C₃-C₆-cycloalkyl group (“fluorinatedC₃-C₆-cycloalkyl-C₁-C₂-alkyl”) as defined above which is bound to theremainder of the molecule via a C₁-C₂-alkyl group, as defined above.

The term “C₁-C₂-alkoxy” is a C₁-C₂-alkyl group, as defined above,attached via an oxygen atom. The term “C₁-C₃-alkoxy” is a C₁-C₃-alkylgroup, as defined above, attached via an oxygen atom. The term“C₁-C₄-alkoxy” is a C₁-C₄-alkyl group, as defined above, attached via anoxygen atom. The term “C₁-C₆-alkoxy” is a C₁-C₆-alkyl group, as definedabove, attached via an oxygen atom. C₁-C₂-Alkoxy is methoxy or ethoxy.C₁-C₃-Alkoxy is additionally, for example, n-propoxy and 1-methylethoxy(isopropoxy). C₁-C₄-Alkoxy is additionally, for example, butoxy,1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or1,1-dimethylethoxy (tert-butoxy). C₁-C₆-Alkoxy is additionally, forexample, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy,1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy,1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy,3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy,2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy,1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxyor 1-ethyl-2-methylpropoxy. C₁-C₈-Alkoxy is additionally, for example,heptyloxy, octyloxy, 2-ethylhexyloxy and positional isomers thereof.

The term “fluorinated C₁-C₂-alkoxy” is a fluorinated C₁-C₂-alkyl group,as defined above, attached via an oxygen atom. The term “fluorinatedC₁-C₃-alkoxy” is a fluorinated C₁-C₃-alkyl group, as defined above,attached via an oxygen atom. The term “fluorinated C₁-C₆-haloalkoxy” isa fluorinated C₁-C₆-alkyl group, as defined above, attached via anoxygen atom. Fluorinated C₁-C₂-alkoxy is, for example, OCH₂F, OCHF₂,OCF₃, 1-fluoroethoxy, (R)-1-fluoroethoxy, (S)-1-fluoroethoxy,2-fluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy,2,2-difluoroethoxy, 1,1,2-trifluoroethoxy, 1,2,2-trifluoroethoxy,2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy or OC₂F₅. FluorinatedC₁-C₃-alkoxy is additionally, for example, 1-fluoropropoxy,(R)-1-fluoropropoxy, (S)-1-fluoropropoxy, 2-fluoropropoxy,(R)-2-fluoropropoxy, (S)-2-fluoropropoxy, 3-fluoropropoxy,1,1-difluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy,3,3-difluoropropoxy, 3,3,3-trifluoropropoxy,(R)-2-fluoro-1-methylethoxy, (S)-2-fluoro-1-methylethoxy,(R)-2,2-difluoro-1-methylethoxy, (S)-2,2-difluoro-1-methylethoxy,(R)-1,2-difluoro-1-methylethoxy, (S)-1,2-difluoro-1-methylethoxy,(R)-2,2,2-trifluoro-1-methylethoxy, (S)-2,2,2-trifluoro-1-methylethoxy,2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy,OCH₂—C₂F₅, OCF₂—C₂F₅ or 1-(CH₂F)-2-fluoroethoxy. FluorinatedC₁-C₄-alkoxy is additionally, for example, 1-fluorobutoxy,(R)-1-fluorobutoxy, (S)-1-fluorobutoxy, 2-fluorobutoxy, 3-fluorobutoxy,4-fluorobutoxy, 1,1-difluorobutoxy, 2,2-difluorobutoxy,3,3-difluorobutoxy, 4,4-difluorobutoxy, 4,4,4-trifluorobutoxy ornonafluorobutoxy. Fluorinated C₁-C₆-alkoxy is additionally, for example,5-fluoropentoxy, undecafluoropentoxy, 6-fluorohexoxy ortridecafluorohexoxy.

The term “C₁-C₄-alkoxy-C₁-C₄-alkyl” as used herein, refers to astraight-chain or branched alkyl group having 1 to 4 carbon atoms, asdefined above, where one hydrogen atom is replaced by a C₁-C₄-alkoxygroup, as defined above. The term “C₁-C₆-alkoxy-C₁-C₄-alkyl” as usedherein, refers to a straight-chain or branched alkyl group having 1 to 4carbon atoms, as defined above, where one hydrogen atom is replaced by aC₁-C₆-alkoxy group, as defined above. Examples are methoxymethyl,ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butoxymethyl,sec-butoxymethyl, isobutoxymethyl, tert-butoxymethyl, 1-methoxyethyl,1-ethoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-n-butoxyethyl,1-sec-butoxyethyl, 1-isobutoxyethyl, 1-tert-butoxyethyl, 2-methoxyethyl,2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl,2-sec-butoxyethyl, 2-isobutoxyethyl, 2-tert-butoxyethyl,1-methoxypropyl, 1-ethoxypropyl, 1-propoxypropyl, 1-isopropoxypropyl,1-n-butoxypropyl, 1-sec-butoxypropyl, 1-isobutoxypropyl,1-tert-butoxypropyl, 2-methoxypropyl, 2-ethoxypropyl, 2-propoxypropyl,2-isopropoxypropyl, 2-n-butoxypropyl, 2-sec-butoxypropyl,2-isobutoxypropyl, 2-tert-butoxypropyl, 3-methoxypropyl, 3-ethoxypropyl,3-propoxypropyl, 3-isopropoxypropyl, 3-n-butoxypropyl,3-sec-butoxypropyl, 3-isobutoxypropyl, 3-tert-butoxypropyl and the like.

The term “fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl” as used herein, refersto a straight-chain or branched alkyl group having 1 to 4 carbon atoms,as defined above, where one hydrogen atom is replaced by a C₁-C₄-alkoxygroup, as defined above, and wherein at least one, e.g. 1, 2, 3, 4 orall of the remaining hydrogen atoms (either in the alkoxy moiety or inthe alkyl moiety or in both) are replaced by fluorine atoms. The term“fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl” as used herein, refers to astraight-chain or branched alkyl group having 1 to 4 carbon atoms, asdefined above, where one hydrogen atom is replaced by a C₁-C₆-alkoxygroup, as defined above, and wherein at least one, e.g. 1, 2, 3, 4 orall of the remaining hydrogen atoms (either in the alkoxy moiety or inthe alkyl moiety or in both) are replaced by fluorine atoms. Examplesare difluoromethoxymethyl (CHF₂OCH₂), trifluoromethoxymethyl,1-difluoromethoxyethyl (CHF₂OCH(CH₃)), 1-trifluoromethoxyethyl(CF₃OCH(CH₃)), 2-difluoromethoxyethyl (CHF₂OCH₂CH₂),2-trifluoromethoxyethyl (CF₃OCH₂CH₂), methoxy-difluoromethyl (CH₃OCF₂),2-methoxy-1,1-difluoroethyl (CH₃OCH₂CF₂), 2-methoxy-2,2-difluoroethyl(CH₃OCF₂CH₂), and the like.

The term “hydroxy-C₁-C₄-alkyl” as used herein, refers to astraight-chain or branched alkyl group having 1 to 4 carbon atoms, asdefined above, where one hydrogen atom is replaced by a hydroxyl group.The term “hydroxy-C₁-C₆-alkyl” as used herein, refers to astraight-chain or branched alkyl group having 1 to 6 carbon atoms, asdefined above, where one hydrogen atom is replaced by a hydroxyl group.Examples for hydroxy-C₁-C₄-alkyl include hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,1-hydroxyprop-2-yl, 2-hydroxyprop-2-yl, 1-hydroxybutyl, 2-hydroxybutyl,3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxybut-2-yl, 2-hydroxybut-2-yl,3-hydroxybut-2-yl, 4-hydroxybut-2-yl, hydroxy-tert-butyl and the like.Examples for hydroxy-C₁-C₆-alkyl are, apart those mentioned forhydroxy-C₁-C₄-alkyl, 1-hydroxypentyl, 2-hydroxypentyl, 3-hydroxypentyl,4-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, 2-hydroxyhexyl,3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 6-hydroxyhexyl and thelike.

The term “hydroxy-C₁-C₄-alkoxy” as used herein, refers to a C₁-C₄-alkoxygroup, as defined above, where one hydrogen atom is replaced by ahydroxy group. The term “hydroxy-C₁-C₆-alkoxy” as used herein, refers toa C₁-C₆-alkoxy group, as defined above, where one hydrogen atom isreplaced by a hydroxy group. Examples for hydroxy-C₁-C₄-alkoxy includehydroxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxypropoxy,2-hydroxypropoxy, 3-hydroxypropoxy, 1-hydroxy-2-propoxy,2-hydroxy-2-propoxy, 1-hydroxybutoxy, 2-hydroxybutoxy, 3-hydroxybutoxy,4-hydroxybutoxy, 1-hydroxy-2-butoxy, 2-hydroxy-2-butoxy,3-hydroxy-2-butoxy, 4-hydroxy-2-butoxy, hydroxy-tert-butoxy and thelike. Examples for hydroxy-C₁-C₆-alkoxy include, apart those mentionedfor hydroxy-C₁-C₄-alkoxy, 1-hydroxypentoxy, 2-hydroxypentoxy,3-hydroxypentoxy, 4-hydroxypentoxy, 5-hydroxypentoxy, 1-hydroxyhexoxy,2-hydroxyhexoxy, 3-hydroxyhexoxy, 4-hydroxyhexoxy, 5-hydroxyhexoxy,6-hydroxyhexoxy and the like.

The term “C₁-C₄-alkoxy-C₁-C₄-alkoxy” as used herein, refers to aC₁-C₄-alkoxy group, as defined above, where one hydrogen atom isreplaced by a C₁-C₄-alkoxy group, as defined above. The term“C₁-C₆-alkoxy-C₁-C₄-alkoxy” as used herein, refers to a C₁-C₄-alkoxygroup, as defined above, where one hydrogen atom is replaced by aC₁-C₆-alkoxy group, as defined above. Examples are methoxymethoxy,ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy,sec-butoxymethoxy, isobutoxymethoxy, tert-butoxymethoxy,1-methoxyethoxy, 1-ethoxyethoxy, 1-propoxyethoxy, 1-isopropoxyethoxy,1-butoxyethoxy, 1-sec-butoxyethoxy, 1-isobutoxyethoxy,1-tert-butoxyethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-propoxyethoxy,2-isopropoxyethoxy, 2-butoxyethoxy, 2-sec-butoxyethoxy,2-isobutoxyethoxy, 2-tert-butoxyethoxy, 1-methoxypropoxy,1-ethoxypropoxy, 1-propoxypropoxy, 1-isopropoxypropoxy, 1-butoxypropoxy,1-sec-butoxypropoxy, 1-isobutoxypropoxy, 1-tert-butoxypropoxy,2-methoxypropoxy, 2-ethoxypropoxy, 2-propoxypropoxy,2-isopropoxypropoxy, 2-butoxypropoxy, 2-sec-butoxypropoxy,2-isobutoxypropoxy, 2-tert-butoxypropoxy, 3-methoxypropoxy,3-ethoxypropoxy, 3-propoxypropoxy, 3-isopropoxypropoxy, 3-butoxypropoxy,3-sec-butoxypropoxy, 3-isobutoxypropoxy, 3-tert-butoxypropoxy and thelike.

The term “C₁-C₂-alkylthio” is a C₁-C₂-alkyl group, as defined above,attached via a sulfur atom. The term “C₁-C₃-alkylthio” refers to aC₁-C₃-alkyl group, as defined above, attached via a sulfur atom. Theterm “C₁-C₄-alkylthio” is a C₁-C₄-alkyl group, as defined above,attached via a sulfur atom. The term “C₁-C₆-alkylthio” refers to aC₁-C₆-alkyl group, as defined above, attached via a sulfur atom. Theterm “C₁-C₁₀-alkylthio” refers to a C₁-C₁₀-alkyl group, as definedabove, attached via a sulfur atom. C₁-C₂-Alkylthio is methylthio orethylthio. C₁-C₃-Alkylthio is additionally, for example, n-propylthio or1-methylethylthio (isopropylthio). C₁-C₄-Alkylthio is additionally, forexample, butylthio, 1-methylpropylthio (sec-butylthio),2-methylpropylthio (isobutylthio) or 1,1-dimethylethylthio(tert-butylthio). C₁-C₆-Alkylthio is additionally, for example,pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio,1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio,1-ethylpropylthio, hexylthio, 1-methylpentylthio, 2-methylpentylthio,3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio,1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio,2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio,2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio,1-ethyl-1-methylpropylthio or 1-ethyl-2-methylpropylthio.

The term “fluorinated C₁-C₂-alkylthio” refers to a fluorinatedC₁-C₂-alkyl group, as defined above, attached via a sulfur atom. Theterm “fluorinated C₁-C₃-alkylthio” refers to a fluorinated C₁-C₃-alkylgroup, as defined above, attached via a sulfur atom. The term“fluorinated C₁-C₄-alkylthio” refers to a fluorinated C₁-C₄-alkyl group,as defined above, attached via a sulfur atom. The term “fluorinatedC₁-C₆-alkylthio” refers to a fluorinated C₁-C₆-alkyl group, as definedabove, attached via a sulfur atom. Fluorinated C₁-C₂-alkylthio refersto, for example, SCH₂F, SCHF₂, SCF₃, 2-fluoroethylthio,2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, or SC₂F₅. FluorinatedC₁-C₃-alkylthio may additionally, for example, include2-fluoropropylthio, 3-fluoropropylthio, 2,2-difluoropropylthio,2,3-difluoropropylthio, 3,3,3-trifluoropropylthio, SCH₂—C₂F₅, SCF₂—C₂F₅or 1-(CH₂F)-2-fluoroethylthio. Fluorinated C₁-C₄-alkylthio mayadditionally, for example, include 4-fluorobutylthio ornonafluorobutylthio. Fluorinated C₁-C₆-alkylthio is additionally, forexample, 5-fluoropentylthio, undecafluoropentylthio, 6-fluorohexylthioor dodecafluorohexylthio.

The term “C₁-C₂-alkylsulfinyl” refers to a C₁-C₂-alkyl group, as definedabove, attached via a sulfinyl [S(O)] group. The term“C₁-C₄-alkylsulfinyl” is a C₁-C₄-alkyl group, as defined above, attachedvia a sulfinyl [S(O)] group. The term “C₁-C₆-alkylsulfinyl” is aC₁-C₆-alkyl group, as defined above, attached via a sulfinyl [S(O)]group. C₁-C₂-Alkylsulfinyl is methylsulfinyl or ethylsulfinyl.C₁-C₄-Alkylsulfinyl is additionally, for example, n-propylsulfinyl,1-methylethylsulfinyl (isopropylsulfinyl), butylsulfinyl,1-methylpropylsulfinyl (sec-butylsulfinyl), 2-methylpropylsulfinyl(isobutylsulfinyl) or 1,1-dimethylethylsulfinyl (tert-butylsulfinyl).C₁-C₆-Alkylsulfinyl is additionally, for example, pentylsulfinyl,1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl,1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl,2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl,1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl,4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl,1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl,1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl,1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl.

The term “fluorinated C₁-C₂-alkylsulfinyl” refers to a fluorinatedC₁-C₂-alkyl group, as defined above, attached via a sulfinyl [S(O)]group. The term “fluorinated C₁-C₃-alkylsulfinyl” refers to afluorinated C₁-C₃-alkyl group, as defined above, attached via a sulfinyl[S(O)] group. The term “fluorinated C₁-C₄-alkylsulfinyl” refers to afluorinated C₁-C₄-alkyl group, as defined above, attached via a sulfinyl[S(O)] group. The term “fluorinated C₁-C₆-alkylsulfinyl” refers to afluorinated C₁-C₆-alkyl group, as defined above, attached via a sulfinyl[S(O)] group. Fluorinated C₁-C₂-alkylsulfinyl is, for example, S(O)CH₂F,S(O)CHF₂, S(O)CF₃, 2-fluoroethylsulfinyl, 2,2-difluoroethylsulfinyl,2,2,2-trifluoroethylsulfinyl, or S(O)C₂F₅. FluorinatedC₁-C₃-alkylsulfinyl may additionally, for example, include2-fluoropropylsulfinyl, 3-fluoropropylsulfinyl,2,2-difluoropropylsulfinyl, 2,3-difluoropropylsulfinyl,3,3,3-trifluoropropylsulfinyl, S(O)CH₂—C₂F₅, S(O)CF₂—C₂F₅ or1-(CH₂F)-2-fluoroethylsulfinyl. Fluorinated C₁-C₄-alkylsulfinyl mayadditionally, for example, include 4-fluorobutylsulfinyl ornonafluorobutylsulfinyl. Fluorinated C₁-C₆-alkylsulfinyl mayadditionally, for example, include 5-fluoropentylsulfinyl,undecafluoropentylsulfinyl, 6-fluorohexylsulfinyl ordodecafluorohexylsulfinyl.

The term “C₁-C₂-alkylsulfonyl” refers to a C₁-C₂-alkyl group, as definedabove, attached via a sulfonyl [S(O)₂] group. The term“C₁-C₄-alkylsulfonyl” refers to a C₁-C₄-alkyl group, as defined above,attached via a sulfonyl [S(O)₂] group. The term “C₁-C₆-alkylsulfonyl” isa C₁-C₆-alkyl group, as defined above, attached via a sulfonyl [S(O)₂]group. C₁-C₂-Alkylsulfonyl refers to a methylsulfonyl or ethylsulfonyl.C₁-C₄-Alkylsulfonyl is additionally, for example, n-propylsulfonyl,1-methylethylsulfonyl (isopropylsulfonyl), butylsulfonyl,1-methylpropylsulfonyl (sec-butylsulfonyl), 2-methylpropylsulfonyl(isobutylsulfonyl) or 1,1-dimethylethylsulfonyl (tert-butylsulfonyl).C₁-C₆-Alkylsulfonyl is additionally, for example, pentylsulfonyl,1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl,1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl,2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl,4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl,1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl,2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl,1-ethyl-1-methylpropylsulfonyl or 1-ethyl-2-methylpropylsulfonyl.

The term “fluorinated C₁-C₂-alkylsulfonyl” refers to a fluorinatedC₁-C₂-alkyl group, as defined above, attached via a sulfonyl [S(O)₂]group. The term “fluorinated C₁-C₃-alkylsulfonyl” refers to afluorinated C₁-C₃-alkyl group, as defined above, attached via a sulfonyl[S(O)₂] group. The term “fluorinated C₁-C₄-alkylsulfonyl” refers to afluorinated C₁-C₄-alkyl group, as defined above, attached via a sulfonyl[S(O)₂] group. The term “fluorinated C₁-C₆-alkylsulfonyl” refers to afluorinated C₁-C₆-alkyl group, as defined above, attached via a sulfonyl[S(O)₂] group. Fluorinated C₁-C₂-alkylsulfonyl is, for example,S(O)₂CH₂F, S(O)₂CHF₂, S(O)₂CF₃, 2-fluoroethylsulfonyl,2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, or S(O)₂C₂F₅.Fluorinated C₁-C₃-alkylsulfonyl is additionally, for example,2-fluoropropylsulfonyl, 3-fluoropropylsulfonyl,2,2-difluoropropylsulfonyl, 2,3-difluoropropylsulfonyl,3,3,3-trifluoropropylsulfonyl, S(O)₂CH₂—C₂F₅, S(O)₂CF₂—C₂F₅ or1-(CH₂F)-2-fluoroethylsulfonyl. Fluorinated C₁-C₄-alkylsulfonyl isadditionally, for example, 4-fluorobutylsulfonyl ornonafluorobutylsulfonyl. Fluorinated C₁-C₆-alkylsulfonyl isadditionally, for example, 5-fluoropentylsulfonyl,undecafluoropentylsulfonyl, 6-fluorohexylsulfonyl ordodecafluorohexylsulfonyl.

C₁-C₄-Alkylcarbonyl refers to a straight-chain or branched alkyl grouphaving from 1 to 4 carbon atoms), which is bound to the remainder of themolecule via a carbonyl group (CO), such as in acetyl, propionyl,isopropylcarbonyl, butylcarbonyl, sec-butylcarbonyl, isobutylcarbonyl,and tert-butylcarbonyl. C₁-C₆-Alkylcarbonyl is a straight-chain orbranched alkyl group having from 1 to 6 carbon atoms, which is bound tothe remainder of the molecule via a carbonyl group (CO). Examplesinclude, apart those listed above for C₁-C₄-alkylcarbonylpentylcarbonyl,hexylcarbonyl and the constitutional isomers thereof.

Fluorinated C₁-C₄-alkylcarbonyl refers to a straight-chain or branchedfluorinated alkyl group having from 1 to 4 carbon atoms as definedabove, which is bound to the remainder of the molecule via a carbonylgroup (CO). Fluorinated C₁-C₆-alkylcarbonyl is a straight-chain orbranched fluorinated alkyl group having from 1 to 6 carbon atoms asdefined above, which is bound to the remainder of the molecule via acarbonyl group (CO). Examples include trifluoromethylcarbonyl,2,2,2-trifluoroethylcarbonyl and the like.

C₃-C₆-cycloalkylcarbonyl relates to a C₃-C₆-cycloalkyl group as definedabove which is bound to the remainder of the molecule via a carbonylgroup (CO), such as in cyclopropylcarbonyl, cyclobutylcarbonyl,cyclopentylcarbonyl and cyclohexylcarbonyl.

C₁-C₆-Alkoxycarbonyl refers to a straight-chain or branched alkoxy grouphaving from 1 to 6, especially 1 to 4 carbon atoms(=C₁-C₄-alkoxycarbonyl), in particular 1 to 3 carbon atoms(=C₁-C₃-alkoxycarbonyl), which is bound to the remainder of the moleculevia a carbonyl group (CO), such as in methoxycarbonyl, ethoxycarbonyl,propyloxycarbonyl, and isopropyloxycarbonyl.

Fluorinated C₁-C₆-alkoxycarbonyl refers to a straight-chain or branchedfluorinated alkoxy group having from 1 to 6, especially 1 to 4 carbonatoms (=fluorinated C₁-C₄-alkoxycarbonyl), in particular 1 to 3 carbonatoms (=fluorinated C₁-C₃-alkoxycarbonyl) as defined above, which isbound to the remainder of the molecule via a carbonyl group (CO).Examples include trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyland the like.

C₁-C₄-Alkylcarbonyloxy refers to a straight-chain or branched alkylgroup having from 1 to 4 carbon atoms, which is bound to the remainderof the molecule via a carbonyloxy group [C(O)—O—], such as inacet(yl)oxy, propionyloxy, isopropylcarbonyloxy, butylcarbonyloxy,sec-butylcarbonyloxy, isobutylcarbonyloxy, and tert-butylcarbonyloxy.C₁-C₆-Alkylcarbonyloxy is a straight-chain or branched alkyl grouphaving from 1 to 6 carbon atoms, which is bound to the remainder of themolecule via a carbonyloxy group [C(O—O—]. Examples include, apart thoselisted above for C₁-C₄-alkylcarbonyloxy, pentylcarbonyloxy,hexylcarbonyloxy and the constitutional isomers thereof.

Fluorinated C₁-C₄-alkylcarbonyloxy refers to a straight-chain orbranched fluorinated alkyl group having from 1 to 4 carbon atoms asdefined above, which is bound to the remainder of the molecule via acarbonyloxy group [C(O)—O—]. Fluorinated C₁-C₆-alkylcarbonyloxy is astraight-chain or branched fluorinated alkyl group having from 1 to 6carbon atoms as defined above, which is bound to the remainder of themolecule via a carbonyloxy group [C(O)—O—]. Examples includetrifluoromethylcarbonyloxy, 2,2,2-trifluoroethylcarbonyloxy and thelike.

Phenyl-C₁-C₂-alkyl is a phenyl group bound to the remainder of themolecule via a C₁-C₂-alkyl group. Examples are benzyl, 1-phenylethyl and2-phenylethyl (phenethyl).

The term “3-, 4-, 5-, 6-, 7- or 8-membered saturated, partiallyunsaturated or maximally unsaturated heterocyclic ring containing 1, 2,3 or 4 heteroatoms or heteroatom groups independently selected from N,O, S, NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups asring members” denotes a 3-, 4-, 5-, 6-, 7- or 8-membered, preferably a3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximumunsaturated heteromonocyclic ring containing 1, 2, 3 or 4 (preferably 1,2 or 3) heteroatoms or heteroatom groups selected from N, O, S, SO andSO₂ and optionally also 1 or 2 C═O and/or C═S groups as ring members.

Unsaturated rings contain at least one C—C and/or C—N and/or N—N doublebond(s). Maximally unsaturated rings contain as many conjugated C—Cand/or C—N and/or N—N double bonds as allowed by the ring size.Maximally unsaturated 5- or 6-membered heterocyclic rings are aromatic.7- and 8-membered rings cannot be aromatic. They are homoaromatic(7-membered ring, 3 double bonds) or have 4 double bonds (8-memberedring). Partially unsaturated rings contain less than the maximum numberof C—C and/or C—N and/or N—N double bond(s) allowed by the ring size.The heterocyclic ring may be attached to the remainder of the moleculevia a carbon ring member or via a nitrogen ring member. As a matter ofcourse, the heterocyclic ring contains at least one carbon ring atom. Ifthe ring contains more than one 0 ring atom, these are not adjacent.

In heterocyclic rings containing N as a ring member this nitrogen atommay either be present as tertiary N formally bound by a double and asingle bond (like in pyridyl) or may be present as secondary NH (if N isnot part of a ring double bond). In case that N is actually present asNH, and the ring is substituted, the substituent may either be bound toa carbon ring atom or to such a secondary nitrogen ring atom. In casethat N is actually present as NH, the ring may either be bound to theremainder of the molecule via a carbon ring atom or such a secondarynitrogen ring atom.

Examples of a 3-, 4-, 5-, 6- or 7-membered saturated heterocyclic ringinclude: Oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl,azetidinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydrofuran-2-on-3-yl, tetrahydrofuran-2-on-4-yl,tetrahydrofuran-2-on-5-yl, tetrahydrofuran-2-thion-3-yl,tetrahydrofuran-2-thion-4-yl, tetrahydrofuran-2-thion-5-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydrothien-2-on-3-yl,tetrahydrothien-2-on-4-yl, tetrahydrothien-2-on-5-yl,tetrahydrothien-2-thion-3-yl, tetrahydrothien-2-thion-4-yl,tetrahydrothien-2-thion-5-yl, pyrrolidin-1-yl, pyrrolidine-2-on-1-yl,pyrrolidine-2,5-dion-1-yl, pyrrolidine-2-thion-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, pyrrolidine-2-on-3-yl, pyrrolidine-2-on-4-yl,pyrrolidine-2-on-5-yl, pyrrolidine-2,5-dion-3-yl,pyrrolidine-2-thion-3-yl, pyrrolidine-2-thion-4-yl,pyrrolidine-2-thion-5-yl, pyrazolidin-1-yl, pyrazolidin-3-yl,pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin-1-yl,imidazolidin-2-on-1-yl, imidazolidin-2-thion-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, imidazolidin-2-on-4-yl, imidazolidin-2-thion-4-yl,oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl,isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl,isoxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl,thiazolidin-5-yl, isothiazolidin-2-yl, isothiazolidin-3-yl,isothiazolidin-4-yl, isothiazolidin-5-yl, 1,2,4-oxadiazolidin-3-yl,1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl,1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl,1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl,1,3,4-triazolidin-1-yl, 1,3,4-triazolidin-2-yl, 2-tetrahydropyranyl,4-tetrahydropyranyl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, piperidin-1-yl,piperidin-2-on-1-yl, piperidin-2,5-dion-1-yl, piperidine-2-thion-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-2-on-3-yl,piperidin-2,5-dion-3-yl, piperidin-2-thion-3-yl, piperidin-4-yl,hexahydropyridazin-3-yl, hexahydropyridazin-4-yl,hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl,hexahydropyrimidin-5-yl, piperazin-1-yl, piperazin-2-yl,1,3,5-hexahydrotriazin-1-yl, 1,3,5-hexahydrotriazin-2-yl and1,2,4-hexahydrotriazin-3-yl, morpholin-2-yl, morpholin-3-yl,morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl,thiomorpholin-4-yl, 1-oxothiomorpholin-2-yl, 1-oxothiomorpholin-3-yl,1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-2-yl,1,1-dioxothiomorpholin-3-yl, 1,1-dioxothiomorpholin-4-yl, azepan-1-,-2-, -3- or -4-yl, oxepan 2-, 3-, -4- or -5-yl,hexahydro-1,3-diazepinyl, hexahydro-1,4-diazepinyl,hexahydro-1,3-oxazepinyl, hexahydro-1,4-oxazepinyl,hexahydro-1,3-dioxepinyl, hexahydro-1,4-dioxepinyl and the like.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered saturated heterocyclicring further include oxocane, thiocane, azocane, [1,3]diazocane,[1,4]diazocane, [1,5]diazocane, [1,5]oxazocane and the like.

Examples of a 3-, 4-, 5-, 6- or 7-membered partially unsaturatedheterocyclic ring include: 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl,2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl,2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl,2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl,2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl,2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl,2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl,2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl,2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl,2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl,2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl,2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl,2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl,3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl,3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl,4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl,4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl,2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl,3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl,2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- ortetrahydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- ortetrahydropyrimidinyl, 4-di- or tetrahydropyrimidinyl, 5-di- ortetrahydropyrimidinyl, di- or tetrahydropyrazinyl, 1,3,5-di- ortetrahydrotriazin-2-yl, 1,2,4-di- or tetrahydrotriazin-3-yl,2,3,4,5-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,3,4,5,6-tetrahydro[2H]azepin-2-, -3-, -4-, -5-, -6- or -7-yl,2,3,4,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,2,3,6,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydrooxepinyl, such as 2,3,4,5-tetrahydro[1H]oxepin-2-, -3-, -4-,-5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6-or -7-yl, 2,3,6,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydro-1,3-diazepinyl, tetrahydro-1,4-diazepinyl,tetrahydro-1,3-oxazepinyl, tetrahydro-1,4-oxazepinyl,tetrahydro-1,3-dioxepinyl and tetrahydro-1,4-dioxepinyl.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered partially unsaturatedheterocyclic ring further include 1,2,3,4,5,6-hexahydroazocine,2,3,4,5,6,7-hexahydroazocine, 1,2,3,4,5,8-hexahydroazocine,1,2,3,4,7,8-hexahydroazocine,1,2,3,4,5,6-hexahydro-[1,5]diazocine,1,2,3,4,7,8-hexahydro-[1,5]diazocineand the like.

Examples of a 3-, 4-, 5-, 6- or 7-membered maximally unsaturated(including aromatic) heterocyclic ring include 5- or 6-memberedheteroaromatic rings, such as 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 2-pyridinyl,3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl,1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl, and also homoaromaticradicals, such as 1H-azepine, 1H-[1,3]-diazepine and 1H-[1,4]-diazepine.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered maximally unsaturatedheterocyclic ring further include [1,3]diazocine, [1,5]diazocine and[1,5]diazocine.

A 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated ormaximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms orheteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═Oand C═S as ring members is either saturated, partially unsaturated andcarbocyclic (if it contains only C═O and/or C═S as heteroatom group andno further heteroatoms or heteroatom groups) or saturated, partiallyunsaturated or maximally unsaturated heterocyclic. Examples are, inaddition to the heterocyclic rings mentioned above, carbocyclic rings,such as cyclopropanonyl, cyclobutanonyl, cyclopentanonyl,cyclohexanonyl, cyclohexandionyl, cycloheptanonyl, cyclooctanonyl,cyclopropanthionyl, cyclobutanthionyl, cyclopentanthionyl,cyclohexanthionyl, cyclohexandithionyl, cycloheptanthionyl,cyclooctanthionyl, cyclopropenonyl, cyclopentenonyl, cyclohexenonyl andthe like.

Examples of a 4-membered saturated heterocyclic ring containing 1heteroatom or heteroatom group selected from N, O, S, NO, SO and SO₂ asring member are oxetan-3-yl, oxetan-4-yl, azetidin-1-yl, azetidin-2-yl,azetidin-3-yl, thietan-2-yl, thietan-3-yl, 1-oxothietan-2-yl,1-oxothietan-3-yl, 1,1-dioxothietan-2-yl and 1,1-dioxothietan-3-yl.

Examples of a 3-, 4-, 5- or 6-membered saturated heterocyclic ringcontaining 1 or 2 heteroatoms or heteroatom groups independentlyselected from N, O, S, NO, SO and SO₂ as ring members are, apart thoselisted above for the 4-membered saturated heterocyclic ring containing 1heteroatom or heteroatom group selected from N, O, S, NO, SO and SO₂ asring member, oxiral-2-yl, aziridin-1-yl, aziridin-2-yl, thiiran-2-yl,1-oxothiiran-2-yl, 1,1-dioxothiiran-2-yl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,pyrrolidin-1-yl, pyrroldin-2-yl, pyrrolidin-3-yl, pyrazolidin-1-yl,pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin-1-yl,imidazolidin-2-yl, imidazolidin-4-yl, oxazolidin-2-yl, oxazolidin-3-yl,oxazolidin-4-yl, oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl,isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl,thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl,isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl,isothiazolidin-5-yl, tetrahydropyranyl, 4-tetrahydropyranyl,1,3-dioxan-5-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl,piperidin-3-yl, piperidin-4-yl, hexahydropyridazin-3-yl,hexahydropyridazin-4-yl, hexahydropyrimidin-2-yl,hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, piperazin-1-yl,piperazin-2-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl,1-oxothiomorpholin-2-yl, 1-oxothiomorpholin-3-yl,1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-2-yl,1,1-dioxothiomorpholin-3-yl and 1,1-dioxothiomorpholin-4-yl.

The remarks made above and in the following with respect to preferredaspects of the invention, e.g. to preferred meanings of the variablesR¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), R^(5b), R⁶, R⁷, R⁸, R⁹,R¹⁰, R^(11a), R^(11b), a and b of compounds I, to preferred compounds Iand to preferred embodiments of the method or the use according to theinvention, apply in each case on their own or in particular tocombinations thereof.

In a preferred embodiment, R¹ is selected from hydrogen and C₁-C₆-alkyl,in particular from hydrogen and methyl, and is specifically hydrogen.

In a preferred embodiment, R² is selected from cyano, nitro,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl andfluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, more preferably from C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinatedC₁-C₄-alkoxy-C₁-C₄-alkyl, even more preferably from C₁-C₆-alkyl andfluorinated C₁-C₆-alkyl, in particular from methyl, ethyl, propyl,isopropyl and CF₃, more particularly from methyl, ethyl and CF₃, and isspecifically methyl or CF₃. Among C₁-C₆-alkoxy-C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl andfluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl radicals R², preference is given toCH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂OCF₃, CH₂CH₂OCF₃,CH₂OCHF₂ and CH₂CH₂OCHF₂.

In a preferred embodiment, R^(3a) and R^(3b), independently of eachother, are selected from hydrogen, cyano, nitro, C₁-C₆-alkyl andfluorinated C₁-C₆-alkyl. More preferably, R^(3a) is selected fromhydrogen, cyano, nitro, C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl, andR^(3b) is hydrogen. Even more preferably, R^(3a) is selected fromhydrogen and methyl and R^(3b) is hydrogen. In particular, both R^(3a)and R^(3b) are hydrogen.

In a preferred embodiment, R^(4a) and R^(4b), independently of eachother, are selected from hydrogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl, orform together a group ═O, or form together a group —(CH₂)_(m)—, where mis 2, 3 or 4, in particular 2 or 3, especially 2, thus forming togethera spiro-bound ring. More preferably, R^(4a) is selected from hydrogen,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl andfluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl and R^(4b) is hydrogen, or R^(4a)and R^(4b) are methyl, or R^(4a) and R^(4b) form together a group—(CH₂)_(m)—, where m is 2, 3 or 4, in particular 2 or 3, especially 2,thus forming together a spiro-bound ring. In a particular embodiment,they are hydrogen.

In a preferred embodiment, R^(5a) is selected from hydrogen, halogen,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl and C₁-C₆-alkoxy-C₁-C₄-alkyl andR^(5b) is hydrogen. In particular, R^(5a) is hydrogen or methyl,specifically hydrogen, and R^(5b) is hydrogen.

Among C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, fluorinatedC₁-C₆-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkylradicals R^(4a), R^(4b) and R^(5b) preference is given to CH₂OCH₃,CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂OCF₃, CH₂CH₂OCF₃, CH₂OCHF₂ andCH₂CH₂OCHF₂.

In one embodiment, R⁶ is C₃-C₆-cycloalkyl which may carry one or more,in particular one, radicals R⁸.

In another embodiment, R⁶ is a 3-, 4-, 5-, 6-, 7- or 8-memberedsaturated, partially unsaturated or maximally unsaturated heterocyclicring containing 1, 2, 3 or 4 heteroatoms or heteroatom groupsindependently selected from N, O, S, NO, SO and SO₂, and optionally also1 or 2 groups C═O and/or C═S, as ring members, where the heterocyclicring may be substituted with one or more substituents R¹⁰.

As a substituent on a cycloalkyl radical R⁶, preferably each R⁸ isindependently selected from the group consisting of halogen, cyano,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl andfluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl. Among C₁-C₄-alkoxy-C₁-C₄-alkyl andfluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl radicals R⁸, preference is given toCH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂OCF₃, CH₂CH₂OCF₃,CH₂OCHF₂ and CH₂CH₂OCHF₂. In particular, R⁸ is halogen, specifically F.

In a preferred embodiment, R⁶ is unsubstituted C₃-C₆-cycloalkyl; i.e. isselected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Inanother preferred embodiment, R⁶ is fluorinated C₃-C₆-cycloalkyl, suchas 1-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl,1-fluorocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl,2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl and the like. Morepreferably, R⁶ is selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 2,2-difluorocyclopropyl or 3,3-difluorocyclobutyl. Inparticular, R⁶ is selected from cyclopropyl and cyclobutyl, and isparticularly preferably cyclopropyl. In another particular embodiment R⁶is 2,2-difluorocyclopropyl.

In an alternatively preferred embodiment, R⁶ is a 3-, 4-, 5- or6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms orheteroatom groups independently selected from N, O, S, NO, SO and SO₂ asring members, where the heterocyclic ring may be substituted with one ormore substituents R¹⁰, where R¹⁰ has one of the above general or, inparticular, one of the below preferred meanings.

In an alternative particular embodiment, R⁶ is a 4-membered saturatedheterocyclic ring containing 1 heteroatom or heteroatom group selectedfrom N, O, S, NO, SO and SO₂, in particular from O, as ring member,where the heterocyclic ring may be substituted with one or moresubstituents R¹⁰, where R¹⁰ has one of the above general or, inparticular, one of the below preferred meanings. Specifically, R⁶ isoxetan-3-yl which may be substituted with one or more, especially one,substituents R¹⁰, where R¹⁰ has one of the above general or, inparticular, one of the below preferred meanings.

In an alternative particular embodiment, R⁶ is a 5- or 6-memberedsaturated heterocyclic ring containing 1 heteroatom or heteroatom groupselected from N, O, S, NO, SO and SO₂, in particular from 0, as ringmember, where the heterocyclic ring may be substituted with one or moresubstituents R¹⁰, where R¹⁰ has one of the above general or, inparticular, one of the below preferred meanings. Specifically, R⁶ istetrahydrofuran-3-yl or tetrahydropyran-4-yl which may be substitutedwith one or more, especially one, substituents R¹⁰, where R¹⁰ has one ofthe above general or, in particular, one of the below preferredmeanings.

As a substituent on a heterocyclic ring R⁶, each R¹⁰ is independentlypreferably selected from the group consisting of halogen, cyano,C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinatedC₁-C₄-alkoxy, more preferably from F, Cl, cyano, CH₃, CF₃, OCH₃ andOCF₃, and in particular from F, CH₃, CF₃, OCH₃ and OCF₃. SpecificallyR¹⁰ is CH₃.

In a preferred embodiment, each R² is independently selected from thegroup consisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinatedC₃-C₈-cycloalkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy. Morepreferably, each R² is independently selected from halogen, C₁-C₄-alkyl,fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinated C₁-C₄-alkoxy, andis in particular fluorine. In an alternative embodiment, each R² isindependently selected from the group consisting of cyano andC₁-C₄-alkoxy-C₁-C₄-alkyl.

In a preferred embodiment, a is 0 or 1. If a is 1, R² is preferablybound in β-position to the nitrogen ring atom carrying R¹.

In particular, a is 0 if R⁶ is carbocyclic, i.e. C₃-C₆-cycloalkyl whichmay carry one or more radicals R⁸; and a is 0 or 1 if R⁶ isheterocyclic, i.e. a 3-, 4-, 5-, 6-, 7- or 8-membered saturated,partially unsaturated or maximally unsaturated heterocyclic ringcontaining 1, 2, 3 or 4 heteroatoms or heteroatom groups independentlyselected from N, O, S, NO, SO and SO₂, and optionally also 1 or 2 groupsC═O and/or C═S, as ring members, where the heterocyclic ring may besubstituted with one or more substituents R¹⁰.

In a preferred embodiment, b is 0 or 1 and specifically 0.

If not specified otherwise in a specific context, R⁹, R¹⁰, R^(11a) andR^(11b) have following preferred meanings:

Preferably each R⁹ is independently selected from the group consistingof hydrogen, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₁-C₆-hydroxyalkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl,C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, and —NR^(11a)R^(11b), whereR^(11a) and R^(11b) have one of the above general or, in particular, oneof the below preferred meanings. In particular, each R⁹ is independentlyselected from the group consisting of hydrogen, C₁-C₄-alkyl, fluorinatedC₁-C₂-alkyl, C₁-C₄-hydroxyalkyl, C₁-C₄-alkoxy, fluorinated C₁-C₂-alkoxy,and —NR^(11a)R^(11b), where R^(11a) and R^(11b) have one of the abovegeneral or, in particular, one of the below preferred meanings.

Preferably, each R¹⁰ is independently selected from the group consistingof halogen, cyano, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxyand fluorinated C₁-C₄-alkoxy, more preferably from F, Cl, cyano, CH₃,CF₃, OCH₃ and OCF₃, and in particular from F, CH₃, CF₃, OCH₃ and OCF₃.

Preferably, R^(11a) and R^(11b), independently of each other andindependently of each occurrence, are selected from the group consistingof hydrogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkylcarbonyland fluorinated C₁-C₆-alkylcarbonyl.

In a particular embodiment, the compounds of the invention are compoundsof formula I.1

-   -   wherein R², R⁶, R⁷ and b have one of the above general or, in        particular, one of the above preferred meanings, and a is 0 or        1.    -   In a more particular embodiment, the compounds of the invention        are compounds of formula I.1.1

-   -   wherein    -   R^(7a) is H, Cl, F or methyl, in particular H or F, specifically        H;    -   a is 0 or 1; and    -   R², R⁶, R⁷ and b have one of the above general or, in        particular, one of the above preferred meanings.        -   In compounds I.1.1 (b−1) is preferably 0.        -   In compounds I.1 and I.1.1 R² is preferably methyl.        -   In compounds I.1 and I.1.1 a is preferably 0 if R⁶ is a            carbocyclic (i.e. cycloalkyl) radical, and is 0 or 1 if R⁶            is heterocyclic.

Examples of preferred compounds are compounds of the following formulaeIa.1 to Ia.36, where the variables have one of the general or preferredmeanings given above. Examples of preferred compounds are the individualcompounds compiled in the tables 1 to 28080 below. Moreover, themeanings mentioned below for the individual variables in the tables areper se, independently of the combination in which they are mentioned, aparticularly preferred embodiment of the substituents in question.

Table 1

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ iscyclopropyl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 2

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-fluorocyclopropyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 3

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is2-fluorocyclopropyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 4

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is2,2-difluorocyclopropyl and the combination of R^(5a), R^(5b) and R^(7a)for a compound corresponds in each case to one row of Table A.

Table 5

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ iscyclobutyl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 6

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-fluorocyclobutyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 7

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is2-fluorocyclobutyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 8

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is3-fluorocyclobutyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 9

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is2,2-difluorocyclobutyl and the combination of R^(5a), R^(5b) and R^(7a)for a compound corresponds in each case to one row of Table A.

Table 10

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is3,3-difluorocyclobutyl and the combination of R^(5a), R^(5b) and R^(7a)for a compound corresponds in each case to one row of Table A.

Table 11

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ iscyclopentyl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 12

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-fluorocyclopentyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 13

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is2-fluorocyclopentyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 14

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is3-fluorocyclopentyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 15

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is2,2-difluorocyclopentyl and the combination of R^(5a), R^(5b) and R^(7a)for a compound corresponds in each case to one row of Table A.

Table 16

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is3,3-difluorocyclopentyl and the combination of R^(5a), R^(5b) and R^(7a)for a compound corresponds in each case to one row of Table A.

Table 17

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ iscyclohexyl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 18

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-fluorocyclohexyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 19

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is2-fluorocyclohexyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 20

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is3-fluorocyclohexyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 21

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is4-fluorocyclohexyl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 22

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ isaziridin-1-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 23

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-(oxetan-3-yl)-aziridin-2-yl and the combination of R^(5a), R^(5b) andR^(7a) for a compound corresponds in each case to one row of Table A.

Table 24

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-(tetrahydrofuran-3-yl)-aziridin-2-yl and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Table 25

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ isoxiran-2-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 26

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ isazetidin-1-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 27

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-(oxetan-3-yl)-azetidin-2-yl and the combination of R^(5a), R^(5b) andR^(7a) for a compound corresponds in each case to one row of Table A.

Table 28

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-(tetrahydrofuran-3-yl)-azetidin-2-yl and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Table 29

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-(oxetan-3-yl)-azetidin-3-yl and the combination of R^(5a), R^(5b) andR^(7a) for a compound corresponds in each case to one row of Table A.

Table 30

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-(tetrahydrofuran-3-yl)-azetidin-2-yl and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Table 31

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ isoxetan-2-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 32

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ isoxetan-3-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 33

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is3-methyloxetan-2-yl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 34

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is3-methyloxetan-3-yl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 35

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is2-methyloxetan-3-yl and the combination of R^(5a), R^(5b) and R^(7a) fora compound corresponds in each case to one row of Table A.

Table 36

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ ispyrrolidin-1-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 37

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-(oxetan-3-yl)-pyrrolidin-2-yl and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Table 38

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-(tetrahydrofuran-3-yl)-azetidin-2-yl and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Table 39

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-(oxetan-3-yl)-pyrrolidin-3-yl and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Table 40

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1-(tetrahydrofuran-3-yl)-pyrrolidin-3-yl and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Table 41

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ istetrahydrofuran-2-yl and the combination of R^(5a), R^(5b) and R^(7a)for a compound corresponds in each case to one row of Table A.

Table 42

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ istetrahydrofuran-3-yl and the combination of R^(5a), R^(5b) and R^(7a)for a compound corresponds in each case to one row of Table A.

Table 43

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is3-(oxetan-3-yl)-oxazolidin-2-yl and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Table 44

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ isoxazolidin-3-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 45

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is3-(oxetan-3-yl)-oxazolidin-4-yl and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Table 46

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is3-(oxetan-3-yl)-oxazolidin-5-yl and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Table 47

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ isisoxazolidin-2-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 48

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is2-(oxetan-3-yl)-isoxazolidin-3-yl and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Table 49

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is2-(oxetan-3-yl)-isoxazolidin-4-yl and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Table 50

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is2-(oxetan-3-yl)-isoxazolidin-5-yl and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Table 51

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ ispiperidin-1-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 52

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is4-(oxetan-3-yl)-piperazine-1-yl and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Table 53

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is4-(tetrahydrofuran-3-yl)-piperazine-1-yl and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Table 54

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ ismorpholin-4-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 55

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ istetrahydropyran-2-yl and the combination of R^(5a), R^(5b) and R^(7a)for a compound corresponds in each case to one row of Table A.

Table 56

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ istetrahydropyran-3-yl and the combination of R^(5a), R^(5b) and R^(7a)for a compound corresponds in each case to one row of Table A.

Table 57

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ istetrahydropyran-4-yl and the combination of R^(5a), R^(5b) and R^(7a)for a compound corresponds in each case to one row of Table A.

Table 58

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1,3-dioxan-2-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 59

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1,3-dioxan-4-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Table 60

Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶ is1,4-dioxan-2-yl and the combination of R^(5a), R^(5b) and R^(7a) for acompound corresponds in each case to one row of Table A.

Tables 61 to 120

Compounds of the formula Ia.1 in which R^(4a) is methyl, R^(4b) is H, R⁶is as defined in tables 1 to 60 and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Tables 121 to 180

Compounds of the formula Ia.1 in which R^(4a) is ethyl, R^(4b) is H, R⁶is as defined in tables 1 to 60 and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Tables 181 to 240

Compounds of the formula Ia.1 in which R^(4a) is CH₂OCH₃, R^(4b) is H,R⁶ is as defined in tables 1 to 60 and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Tables 241 to 300

Compounds of the formula Ia.1 in which R^(4a) is CH₂OCH₂CH₃, R^(4b) isH, R⁶ is as defined in tables 1 to 60 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 301 to 360

Compounds of the formula Ia.1 in which R^(4a) is CH₂CH₂OCH₃, R^(4b) isH, R⁶ is as defined in tables 1 to 60 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 361 to 420

Compounds of the formula Ia.1 in which R^(4a) is CH₂CH₂OCH₂CH₃, R^(4b)is H, R⁶ is as defined in tables 1 to 60 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 421 to 480

Compounds of the formula Ia.1 in which R^(4a) is CH₂OCHF₂, R^(4b) is H,R⁶ is as defined in tables 1 to 60 and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Tables 481 to 540

Compounds of the formula Ia.1 in which R^(4a) is CH₂OCF₃, R^(4b) is H,R⁶ is as defined in tables 1 to 60 and the combination of R^(5a), R^(5b)and R^(7a) for a compound corresponds in each case to one row of TableA.

Tables 541 to 600

Compounds of the formula Ia.1 in which R^(4a) is CH₂CH₂OCHF₂, R^(4b) isH, R⁶ is as defined in tables 1 to 60 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 601 to 660

Compounds of the formula Ia.1 in which R^(4a) is CH₂CH₂OCF₃, R^(4b) isH, R⁶ is as defined in tables 1 to 60 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 661 to 720

Compounds of the formula Ia.1 in which R^(4a) is methyl, R^(4b) ismethyl, R⁶ is as defined in tables 1 to 60 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 721 to 780

Compounds of the formula Ia.1 in which R^(4a) and R^(4b) form together—CH₂—CH₂—, R⁶ is as defined in tables 1 to 60 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 781 to 1560

Compounds of the formula Ia.2 in which the combination of R^(4a), R^(4b)and R⁶ is as defined in tables 1 to 780 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 1561 to 2340

Compounds of the formula Ia.3 in which the combination of R^(4a), R^(4b)and R⁶ is as defined in tables 1 to 780 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 2341 to 3120

Compounds of the formula Ia.4 in which the combination of R^(4a), R^(4b)and R⁶ is as defined in tables 1 to 780 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 3121 to 3900

Compounds of the formula Ia.5 in which the combination of R^(4a), R^(4b)and R⁶ is as defined in tables 1 to 780 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 3901 to 4680

Compounds of the formula Ia.6 in which the combination of R^(4a), R^(4b)and R⁶ is as defined in tables 1 to 780 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 4681 to 5460

Compounds of the formula Ia.7 in which the combination of R^(4a), R^(4b)and R⁶ is as defined in tables 1 to 780 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 5461 to 6240

Compounds of the formula Ia.8 in which the combination of R^(4a), R^(4b)and R⁶ is as defined in tables 1 to 780 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 6241 to 7020

Compounds of the formula Ia.9 in which the combination of R^(4a), R^(4b)and R⁶ is as defined in tables 1 to 780 and the combination of R^(5a),R^(5b) and R^(7a) for a compound corresponds in each case to one row ofTable A.

Tables 7021 to 7800

Compounds of the formula Ia.10 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 7801 to 8580

Compounds of the formula Ia.11 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 8581 to 9360

Compounds of the formula Ia.12 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 9361 to 10140

Compounds of the formula Ia.13 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 10141 to 10920

Compounds of the formula Ia.14 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 10921 to 11700

Compounds of the formula Ia.15 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 11701 to 12480

Compounds of the formula Ia.16 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 12481 to 13260

Compounds of the formula Ia.17 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 13261 to 14040

Compounds of the formula Ia.18 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 14041 to 14820

Compounds of the formula Ia.19 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 14821 to 15600

Compounds of the formula Ia.20 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 15601 to 16380

Compounds of the formula Ia.21 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 16381 to 17160

Compounds of the formula Ia.22 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 17161 to 17940

Compounds of the formula Ia.23 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 17941 to 18720

Compounds of the formula Ia.24 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 18721 to 19500

Compounds of the formula Ia.25 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 19501 to 20280

Compounds of the formula Ia.26 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 20281 to 21060

Compounds of the formula Ia.27 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 21061 to 21840

Compounds of the formula Ia.28 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 21841 to 22620

Compounds of the formula Ia.29 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 22621 to 23400

Compounds of the formula Ia.30 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 23401 to 24180

Compounds of the formula Ia.31 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 24181 to 24960

Compounds of the formula Ia.32 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 24961 to 25740

Compounds of the formula Ia.33 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 25741 to 26520

Compounds of the formula Ia.34 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 26521 to 27300

Compounds of the formula Ia.35 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

Tables 27301 to 28080

Compounds of the formula Ia.36 in which the combination of R^(4a),R^(4b) and R⁶ is as defined in tables 1 to 780 and the combination ofR^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to onerow of Table A.

TABLE A No. R^(7a) R^(5a) R^(5b) A-1 H H H A-2 F H H A-3 Cl H H A-4 CH₃H H A-5 CHF₂ H H A-6 CF₃ H H A-7 OCH₃ H H A-8 OCHF₂ H H A-9 OCF₃ H HA-10 cyclopropyl H H A-11 CN H H A-12 CH₂OCH₃ H H A-13 CH₂CH₂OCH₃ H HA-14 H CH₃ H A-15 F CH₃ H A-16 Cl CH₃ H A-17 CH₃ CH₃ H A-18 CHF₂ CH₃ HA-19 CF₃ CH₃ H A-20 OCH₃ CH₃ H A-21 OCHF₂ CH₃ H A-22 OCF₃ CH₃ H A-23cyclopropyl CH₃ H A-24 CN CH₃ H A-25 CH₂OCH₃ CH₃ H A-26 CH₂CH₂OCH₃ CH₃ HA-27 H CH₂CH₃ H A-28 F CH₂CH₃ H A-29 Cl CH₂CH₃ H A-30 CH₃ CH₂CH₃ H A-31CHF₂ CH₂CH₃ H A-32 CF₃ CH₂CH₃ H A-33 OCH₃ CH₂CH₃ H A-34 OCHF₂ CH₂CH₃ HA-35 OCF₃ CH₂CH₃ H A-36 cyclopropyl CH₂CH₃ H A-37 CN CH₂CH₃ H A-38CH₂OCH₃ CH₂CH₃ H A-39 CH₂CH₂OCH₃ CH₂CH₃ H A-40 H CH₂OCH₃ H A-41 FCH₂OCH₃ H A-42 Cl CH₂OCH₃ H A-43 CH₃ CH₂OCH₃ H A-44 CHF₂ CH₂OCH₃ H A-45CF₃ CH₂OCH₃ H A-46 OCH₃ CH₂OCH₃ H A-47 OCHF₂ CH₂OCH₃ H A-48 OCF₃ CH₂OCH₃H A-49 cyclopropyl CH₂OCH₃ H A-50 CN CH₂OCH₃ H A-51 CH₂OCH₃ CH₂OCH₃ HA-52 CH₂CH₂OCH₃ CH₂OCH₃ H A-53 H CH₂OCH₂CH₃ H A-54 F CH₂OCH₂CH₃ H A-55Cl CH₂OCH₂CH₃ H A-56 CH₃ CH₂OCH₂CH₃ H A-57 CHF₂ CH₂OCH₂CH₃ H A-58 CF₃CH₂OCH₂CH₃ H A-59 OCH₃ CH₂OCH₂CH₃ H A-60 OCHF₂ CH₂OCH₂CH₃ H A-61 OCF₃CH₂OCH₂CH₃ H A-62 cyclopropyl CH₂OCH₂CH₃ H A-63 CN CH₂OCH₂CH₃ H A-64CH₂OCH₃ CH₂OCH₂CH₃ H A-65 CH₂CH₂OCH₃ CH₂OCH₂CH₃ H A-66 H CH₂CH₂OCH₃ HA-67 F CH₂CH₂OCH₃ H A-68 Cl CH₂CH₂OCH₃ H A-69 CH₃ CH₂CH₂OCH₃ H A-70 CHF₂CH₂CH₂OCH₃ H A-71 CF₃ CH₂CH₂OCH₃ H A-72 OCH₃ CH₂CH₂OCH₃ H A-73 OCHF₂CH₂CH₂OCH₃ H A-74 OCF₃ CH₂CH₂OCH₃ H A-75 cyclopropyl CH₂CH₂OCH₃ H A-76CN CH₂CH₂OCH₃ H A-77 CH₂OCH₃ CH₂CH₂OCH₃ H A-78 CH₂CH₂OCH₃ CH₂CH₂OCH₃ HA-79 H CH₂CH₂OCH₂CH₃ H A-80 F CH₂CH₂OCH₂CH₃ H A-81 Cl CH₂CH₂OCH₂CH₃ HA-82 CH₃ CH₂CH₂OCH₂CH₃ H A-83 CHF₂ CH₂CH₂OCH₂CH₃ H A-84 CF₃CH₂CH₂OCH₂CH₃ H A-85 OCH₃ CH₂CH₂OCH₂CH₃ H A-86 OCHF₂ CH₂CH₂OCH₂CH₃ HA-87 OCF₃ CH₂CH₂OCH₂CH₃ H A-88 cyclopropyl CH₂CH₂OCH₂CH₃ H A-89 CNCH₂CH₂OCH₂CH₃ H A-90 CH₂OCH₃ CH₂CH₂OCH₂CH₃ H A-91 CH₂CH₂OCH₃CH₂CH₂OCH₂CH₃ H A-92 H CH₃ CH₃ A-93 F CH₃ CH₃ A-94 Cl CH₃ CH₃ A-95 CH₃CH₃ CH₃ A-96 CHF₂ CH₃ CH₃ A-97 CF₃ CH₃ CH₃ A-98 OCH₃ CH₃ CH₃ A-99 OCHF₂CH₃ CH₃ A-100 OCF₃ CH₃ CH₃ A-101 cyclopropyl CH₃ CH₃ A-102 CN CH₃ CH₃A-103 CH₂OCH₃ CH₃ CH₃ A-104 CH₂CH₂OCH₃ CH₃ CH₃ A-105 H CH₂CH₃ CH₃ A-106F CH₂CH₃ CH₃ A-107 Cl CH₂CH₃ CH₃ A-108 CH₃ CH₂CH₃ CH₃ A-109 CHF₂ CH₂CH₃CH₃ A-110 CF₃ CH₂CH₃ CH₃ A-111 OCH₃ CH₂CH₃ CH₃ A-112 OCHF₂ CH₂CH₃ CH₃A-113 OCF₃ CH₂CH₃ CH₃ A-114 cyclopropyl CH₂CH₃ CH₃ A-115 CN CH₂CH₃ CH₃A-116 CH₂OCH₃ CH₂CH₃ CH₃ A-117 CH₂CH₂OCH₃ CH₂CH₃ CH₃

Among the above compounds, preference is given to compounds Ia.1 andIa.10; the latter especially if R⁶ is a heterocyclic ring, for examplesas defined in table 22 to 60.

In a specific embodiment, the invention relates to compounds I selectedfrom the compounds of the examples, either in form of free bases or ofany pharmaceutically acceptable salt thereof or a steroisomer, theracemate or any mixture of stereoisomers thereof.

The compounds of the present invention can be prepared by using routinetechniques familiar to a skilled person. In particular, the compounds ofthe formula I can be prepared according to the following schemes,wherein the variables, if not stated otherwise, are as defined above.

Compounds of formula I wherein R^(4b) and R^(5b) are H (=compounds I′)can be synthesized as described in scheme 1 below. The readily availablequinoline 1 in which X is a leaving group, such as Cl, Br I or triflate,is reacted with a suitable boron compound of R⁶, such as R⁶-boronic acid(R⁶—B(OH)₂) or the potassium (trifluoro)borate of R⁶ (e.g. potassiumcyclobutyl(trifluoro)borate or potassium cyclopropyl(trifluoro)borate)in a Suzuki coupling reaction to 2. The reaction is carried out in thepresence of a Pd catalyst, such as Pd(OAc)₂, in general in the presenceof a phosphine ligand (e.g. tricyclohexylphosphine;di(adamantan-1-yl)(butyl)-phosphine etc.), ortetrakis(triphenylphosphine)palladium(0) and the like. Quinoline 2 isthen N-alkylated with a suitable protective group, such as benzyl, e.g.by reaction with benzyl bromide, to 3. Reduction of the quinoliniumcompound 3 with a suitable reduction agent, such as sodium borohydrideand H₂/Raney nickel, yields the 1,2,3,4-tetrahydroquinoline 4, which isthen deprotected to 5. Reaction with the 2-halogenoacetamide 6, whereinY is Cl, Br or I, affords the acetamide 7, the keto group of which isreduced with common reduction agents, like borane,borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex orborohydrides such as sodium borohydride or LAH (lithium aluminiumhydride) or DIBAL-H (diisobutyl aluminium hydride), to 8. Cyclizationwith formaldehyde/aldehyde/ketone 9 (C(O)R^(3a)R^(3b)=formaldehyde ifR^(3a) and R^(3b) are hydrogen; another aldehyde if R^(3a) is hydrogenand R^(3b) is (fluorinated) alkyl, hydroxyalkyl, (fluorinated) alkenyl,(fluorinated) alkynyl, (fluorinated) cycloalkyl, phenyl, phenyl-alkyl ora heterocyclic ring; a ketone if R^(3a) and R^(3b) are (fluorinated)alkyl, hydroxyalkyl, (fluorinated) alkenyl, (fluorinated) alkynyl,(fluorinated) cycloalkyl, phenyl, phenyl-alkyl or a heterocyclic ring),generally in the presence of a strong acid, such as trifluoroaceticacid, yields I′. Alternatively, 2 can be reacted with the2-halogenoacetamide 6 to 10, which is then reduced to 7.

Compounds of formula I wherein R^(4a), R^(4b) and R^(5b) are H(=compounds I″) can alternatively be synthesized as described in scheme2 below. The boronic acid 11 and the α,β-unsaturated ester 12 arereacted in a 1,4-addition in the presence of a Rhodium catalyst, e.g.[RhOH(COD)]₂ or Rh(acac)(CO)₂, if desired in the presence of a phosphineligand, such as 1,4-bis(diphenylphosphino)butane (dppb), followed bylactam formation. The lactam 13 is then reduced with common reductionagents, like borane, borane-tetrahydrofurane-complex,borane-dimethylsulfide-complex or borohydrides such as sodiumborohydride, to the tetrahydroquinoline 14. Like in the reactionsequence of scheme 1, reaction with the 2-halogenoacetamide 6, wherein Yis C1, Br or I, affords the acetamide 15, the keto group of which isreduced with common reduction agents, like borane,borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex orborohydrides such as sodium borohydride or LAH (lithium aluminiumhydride) or DIBAL-H (diisobutyl aluminium hydride), to 16. Cyclizationwith formaldehyde/aldehyde/ketone 9, generally in the presence of astrong acid, such as trifluoroacetic acid, yields I″.

For obtaining compounds I wherein R^(4a) and R^(4b) form together ═O,the lactam 13 is not reduced, but is directly reacted with the2-halogenoacetamide 6 to 17, followed by reduction of the CO group inthe amide to 18 and finally cyclisation, as shown in scheme 3 below.Alternatively, compounds I′″ can be obtained as described below scheme4.

Compounds of formula I wherein R^(4a), R^(4b) and R^(5b) are H(=compounds I″) can alternatively be synthesized as described in scheme4 below. The protected tetrahydrobenzodiazepine 19, wherein Z is ahydrogen or a halogen atom, such as Cl, Br or I and PG is a commonprotective group, such as a carbamate, especially boc, is acylated withthe acrylic acid derivative 20, wherein LG is an appropriate leavinggroup, such as Cl or an anhydride or a chloroformate, in the presence ofa base, such as triethylamine or Hünig's base, in an organic solvent,such as ether or methylene chloride. Reaction of 21 with a Lewis acid ora Brönstedt acid HA or irradiation with a suitable wavelength commonlyderived from a mercury lamp in an adequate solvent, such as acetone ortoluene, in a common photoreactor yields cyclization to 22. Reduction ofthe carbonyl group with common reduction agents like borohydrides suchas sodium borohydride or borane-tetrahydrofurane-complex yields 23,which is deprotected using suitable reagents such as strong bases oracids to I″, wherein R^(4a) and R^(4b) and R^(5b) are H. Compounds I″″wherein R^(4a) and R^(4b) form together ═O can be obtained by skippingthe reduction step to 23 and deprotecting 22.

Alternatively, compound 22 can be directly synthesized by reacting thetetrahydrobenzodiazepine 19, wherein Z is —B(OH)₂ with the acrylic acidderivative 20 in a 1,4-addition in the presence of a Rhodium catalyst,e.g. [RhOH(COD)]₂ or Rh(acac)(CO)₂, if desired in the presence of aphosphine ligand, such as 1,4-bis(diphenylphosphino)butane (dppb),followed by lactam formation to 22. This is then further reacted asdescribed above.

If compound 22 is deprotected, this yields compound I″′ as well as othercompounds I in which (R²)_(a) is not necessarily bound to the sameposition as in compounds I″′.

If desired, substituents R¹ different from hydrogen can be introducedfor example via alkylation under typical conditions such as stirring inan appropriate solvent in the presence of an alkylhalide and a base orvia other common substitution reactions, or via reductive aminationusing a suitable aldehyde or ketone in the presence of reduction agent,such as borohydrides, e.g. triacetoxyborohydride, sodiumcyanoborohydride or sodium borohydride. —C(═O)R⁹ as radical R¹ can beintroduced via amidation under typical amidation conditions, e.g. viareaction with a compound X—C(═O)R⁹, where X is OH or a halogen atom,under heating and removal of reaction water or using a coupling reagent,such as DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide),HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), HBTU((0-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), HCTU(1H-benzotriazolium-1-[bis(dimethylamino)methylene]-5-chlorotetrafluoroborate), BOP((benzotriazol-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate), Py-BOP((benzotriazol-1-yloxy)-tripyrrolidinphosphonium hexafluorophosphate) orPy-BrOP (bromotripyrrolidinphosphonium hexafluorophosphate.

Compounds I wherein R^(5b) is different from H can be prepared, forexample, by reacting compound 22 with a compound LG-R^(5b) in thepresence of a base, wherein LG is an appropriate leaving group, such asCl or Br.

Alternatively to the method depicted in scheme 4, compounds I whereinR^(4a), R^(4b) and R^(5b) are H (=compounds I″) can be synthesized asdescribed in scheme 5 below. Readily available anilines 24 arederivatized with carbonyl moieties 25 by acylation procedures employingappropriate leaving groups LG, such as chlorides or anhydrides, in thepresence of a base such as triethylamine or Hünig's base, in an organicsolvent, such as diethyl ether or methylene chloride to yield 26.Cyclization products 13 are received by irradiation with a suitablewavelength commonly derived from a mercury lamp in an adequate solventsuch as acetone or toluene in a common photoreactor known to thoseskilled in the art. These are further reacted as depicted in schemes 2and 3.

Compounds I wherein R^(4a) and R^(4b) are not H or do not form togethera group ═O can be prepared by standard derivatization methods ofcompounds wherein R^(4a) and R^(4b) form together a group ═O. Forinstance, compounds wherein R^(4a) and R^(4b) form together a group ═Smay be prepared by reaction with a sulfurization agent, such asLawesson's reagent or P₂S₅. Alkyl and related groups as radicals R^(4a)and R^(4b) may be introduced via Grignard reduction Amino and relatedgroups may be introduced via reductive amination. Hydroxyl group R^(4a)or R^(4b) may be introduced by reducing the carbonyl group. This may bealkylated to yield alkoxy and related groups R^(4a) and R^(4b) orsubstituted by diverse groups.

If not otherwise indicated, the above-described reactions are generallycarried out in a solvent at temperatures between room temperature andthe boiling temperature of the solvent employed. Alternatively, theactivation energy which is required for the reaction can be introducedinto the reaction mixture using microwaves, something which has provedto be of value, in particular, in the case of the reactions catalyzed bytransition metals (with regard to reactions using microwaves, seeTetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a generalmanner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH2002.

The acid addition salts of compounds I are prepared in a customarymanner by mixing the free base with a corresponding acid, whereappropriate in solution in an organic solvent, for example a loweralcohol, such as methanol, ethanol or propanol, an ether, such as methyltert-butyl ether or diisopropyl ether, a ketone, such as acetone ormethyl ethyl ketone, or an ester, such as ethyl acetate.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the preparation methods are within routinetechniques.

Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protective Groups in OrganicSynthesis (3^(rd) ed.), John Wiley & Sons, N.Y. (1999), which is hereinincorporated by reference in its entirety. Synthesis of the compounds ofthe invention may be accomplished by methods analogous to thosedescribed in the synthetic schemes described hereinabove and in specificexamples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

The present invention further relates to a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compound Ias defined above or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof, in combination with at leastone pharmaceutically acceptable carrier and/or auxiliary substance.

The present invention further relates to a compound I as defined aboveor an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for use as a medicament.

The present invention also relates to a compound I as defined above oran N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for the treatment of disorders which respond tothe modulation of the 5-HT_(2C) receptor.

The present invention also relates to the use of a compound I as definedabove or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders which respond to themodulation of the 5-HT_(2C) receptor, and to a method for treatingdisorders which respond to the modulation of the 5-HT_(2C) receptor,which method comprises administering to a subject in need thereof atleast one compound I as defined above or an N-oxide, a tautomeric form,a stereoisomer or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are modulators of the 5-HT_(2C)receptor. Specifically, the compounds of formula I are agonists orpartial agonists of the 5-HT_(2C) receptor. Thus, in a specificembodiment, the invention relates to a compound I as defined above or anN-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for the treatment of disorders which respond to5-HT_(2C) receptor agonists, further to the use of a compound I asdefined above or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders which respond to 5-HT_(2C)receptor agonists, and to a method for treating disorders which respondto 5-HT_(2C) receptor agonists, which method comprises administering toa subject in need thereof at least one compound I as defined above or anN-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof.

Within the meaning of the invention, the term “disorder” denotesdisturbances and/or anomalies which are as a rule regarded as beingpathological conditions or functions and which can manifest themselvesin the form of particular signs, symptoms and/or malfunctions. While thetreatment according to the invention can be directed toward individualdisorders, i.e. anomalies or pathological conditions, it is alsopossible for several anomalies, which may be causatively linked to eachother, to be combined into patterns, i.e. syndromes, which can betreated in accordance with the invention.

In one aspect of the invention, the diseases to be treated are disordersare damage of the central nervous system, disorders of the centralnervous system, eating disorders, ocular hypertension, cardiovasculardisorders, gastrointestinal disorders and diabetes.

Disorders or diseases of the central nervous system are understood asmeaning disorders which affect the spinal cord and, in particular, thebrain. These are, for example, cognitive dysfunction, attention deficitdisorder/hyperactivity syndrome and cognitive deficits related withschizophrenia, attention deficit/hyperactivity syndrome, personalitydisorders, affective disorders, motion or motor disorders, pain,migraine, sleep disorders (including disturbances of the Circadianrhythm), feeding disorders, diseases associated with neurodegeneration,addiction diseases, obesity or psoriasis.

Examples of cognitive dysfunction are deficits in memory, cognition, andlearning, Alzheimer's disease, age-related cognitive decline, and mildcognitive impairment, or any combinations thereof. Examples ofpersonality disorders are schizophrenia and cognitive deficits relatedto schizophrenia. Examples of affective disorders are depression,anxiety, bipolar disorder and obsessive compulsive disorders, or anycombination thereof. Examples of motion or motor disorders areParkinson's disease and epilepsy. Examples of feeding disorders areobesity, bulimia, weight loss and anorexia, especially anorexia nervosa.Examples of diseases associated with neurodegeneration are stroke,spinal or head trauma, and head injuries, such as hydrocephalus.

Pain condition includes nociceptive pain, neuropathic pain or acombination thereof. Such pain conditions or disorders can include, butare not limited to, post-operative pain, osteoarthritis pain, pain dueto inflammation, rheumatoid arthritis pain, musculoskeletal pain, burnpain (including sunburn), ocular pain, the pain associated with dentalconditions (such as dental caries and gingivitis), post-partum pain,bone fracture, herpes, HIV, traumatic nerve injury, stroke,post-ischemia, fibromyalgia, reflex sympathetic dystrophy, complexregional pain syndrome, spinal cord injury, sciatica, phantom limb pain,diabetic neuropathy, hyperalgesia and cancer.

In certain other embodiments, the disease condition is bladderdysfunction, including urinary incontinence.

Diabetes includes diabetes insipidus, diabetes mellitus, type Idiabetes, type II diabetes, type III diabetes, diabetes secondary topancreatic diseases, diabetes related to steroid use, diabetescomplications, hyperglycemia and insulin resistance.

The addiction diseases include psychiatric disorders and behavioraldisturbances which are caused by the abuse of psychotropic substances,such as pharmaceuticals or narcotics, and also other addiction diseases,such as addiction to gaming (impulse control disorders not elsewhereclassified). Examples of addictive substances are: opioids (e.g.morphine, heroin and codeine), cocaine; nicotine; alcohol; substanceswhich interact with the GABA chloride channel complex, sedatives,hypnotics and tranquilizers, for example benzodiazepines; LSD;cannabinoids; psychomotor stimulants, such as3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamine andamphetamine-like substances such as methylphenidate, other stimulantsincluding caffeine and nicotine. Addictive substances which comeparticularly into consideration are opioids, cocaine, amphetamine oramphetamine-like substances, nicotine and alcohol. Especially, addictiondisorders include alcohol abuse, cocaine abuse, tobacco abuse andsmoking cessation.

With regard to the treatment of addiction diseases, particularpreference is given to those compounds according to the invention of theformula (I) which themselves do not possess any psychotropic effect.This can also be observed in a test using rats, which, after having beenadministered compounds which can be used in accordance with theinvention, reduce their self administration of psychotropic substances,for example cocaine.

Examples of gastrointestinal disorders are irritable bowel syndrome.

Preferably, the disorders are selected from the group consisting ofbipolar disorder, depression, atypical depression, mood episodes,adjustment disorders, anxiety, panic disorders, post-traumatic syndrome,psychoses, schizophrenia, cognitive deficits of schizophrenia, memoryloss, dementia of aging, Alzheimer's disease, neuropsychiatric symptomsin Alzheimer's disease (e.g. aggression), behavioral disordersassociated with dementia, social phobia, mental disorders in childhood,attention deficit hyperactivity disorder, organic mental disorders,autism, mutism, disruptive behavior disorder, impulse control disorder,borderline personality disorder, obsessive compulsive disorder, migraineand other conditions associated with cephalic pain or other pain, raisedintracranial pressure, seizure disorders, epilepsy, substance usedisorders, alcohol abuse, cocaine abuse, tobacco abuse, smokingcessation, sexual dysfunction/erectile dysfunction in males, sexualdysfunction in females, premenstrual syndrome, late luteal phasesyndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea,chronic fatigue syndrome, psoriasis, Parkinson's disease, psychosis inParkinson's disease, neuropsychiatric symptoms in Parkinson's disease(e.g. aggression), Lewy Body dementia, neuropsychiatric symptoms in LewyBody dementia (e.g. aggression), spinal cord injury, trauma, stroke,pain, bladder dysfunction/urinary incontinence, encephalitis,meningitis, eating disorders, obesity, bulimia, weight loss, anorexianervosa, ocular hypertension, cardiovascular disorders, gastrointestinaldisorders, diabetes insipidus, diabetes mellitus, type I diabetes, typeII diabetes, type III diabetes, diabetes secondary to pancreaticdiseases, diabetes related to steroid use, diabetes complications,hyperglycemia and insulin resistance, and are specificallyschizophrenia, depression, bipolar disorders, obesity, substance usedisorders, neuropsychiatric symptoms in Alzheimer's disease (e.g.aggression) or neuropsychiatric symptoms in Parkinson's disease (e.g.aggression).

The compounds of the invention may be used for a preventive treatment(prophylaxis), in particular as relapse prophylaxis or phaseprophylaxis, but are preferably used for a treatment in its proper sense(i.e. non-prophylactic), i.e. for the treatment of acute or chronicsigns, symptoms and/or malfunctions. The treatment can be orientatedsymptomatically, for example as the suppression of symptoms. It can beeffected over a short period, be orientated over the medium term or canbe a long-term treatment, for example within the context of amaintenance therapy.

In another embodiment, the present invention relates to the use of acompound I as defined above or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof for preparinga medicament for preventing (the development of) a disease condition asdescribed above and to a method for preventing (the development of) adisease condition as described above comprises administering to thesubject in need of treatment thereof (e.g., a mammal, such as a human) atherapeutically effective amount of a compound I as defined above or anN-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof. As used herein, the term “prevent” a diseasecondition by administration of any of the compounds described hereinmeans that the detectable physical characteristics or symptoms of thedisease or condition do not develop following the administration of thecompound described herein. Alternatively, the method comprisesadministering to the subject a therapeutically effective amount of acompound I as defined above or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of at least onecognitive enhancing drug.

In yet another embodiment, the present invention relates to the use acompound I as defined above or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof for preparinga medicament for preventing the progression (e.g., worsening) of adisease condition and to a method for preventing the progression (e.g.,worsening) of a disease condition, which method comprises administeringto the subject in need of treatment thereof (e.g., a mammal, such as ahuman) a therapeutically effective amount of a compound I as definedabove or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof.

There are several lines of evidence suggesting that 5-HT_(2C) agonistsor partial agonists would have therapeutic use in a variety of diseases,disorders and conditions.

Knockout mice models lacking the 5-HT_(2C) receptor exhibit hyperphagia,obesity and are more prone to seizures and sudden death [Tecott L H, SunL M, Akana S F, Strack A M, Lowenstein D H, Dallman M F, Julius D (1995)Eating disorder and epilepsy in mice lacking 5-HT_(2C) serotoninreceptors. Nature 374:542-546]. They also exhibit compulsive-likebehavior [Chou-Green J M, Holscher T D, Dallman M F, Akana S F (2003).Compulsive behavior in the 5-HT_(2C) receptor knockout mouse. Phys.Behav. 78:641-649], hyperresponsiveness to repeated stress [Chou-Green JM, Holscher T D, Dallman M F, Akana S F (2003). Repeated stress in youngand old 5-HT_(2C) receptor knockout mouse. Phys. Behav. 79:217-226],wakefulness [Frank M G, Stryker M P, Tecott L H (2002). Sleep and sleephomeostasis in mice lacking the 5-HT_(2C) receptor.Neuropsychopharmacology 27:869-873], hyperactivity and drug dependence[Rocha B A, Goulding E H, O'Dell L E, Mead A N, Coufal N G, Parsons L H,Tecott L H (2002). Enhanced locomotor, reinforcing and neurochemicaleffects of cocaine in serotonin 5-hydroxytryptamine 2C receptor mutantmice. J. Neurosci. 22:10039-10045].

5-HT_(2C) is unique among other G-protein-coupled receptors (GPCRs) inthat its pre-mRNA is a substrate for base modification via hydrolyticdeamination of adenosines to yield inosines. Five adenosines, locatedwithin a sequence encoding the putative second intracellular domain canbe converted to inosines. This editing can alter the coding potential ofthe triplet codons and allows for the generation of multiple differentreceptor isoforms. The edited receptor isoforms were shown to havereduced ability to interact with G-proteins in the absence of agoniststimulation [Werry, T D, Loiacono R, Sexton Pa., Christopoulos A (2008).RNA editing of the serotonin 5-HT_(2C) receptor and its effects on cellsignaling, pharmacology and brain function. Pharmac. Therap. 119:7-23].

Edited 5-HT_(2C) isoforms with reduced function are significantlyexpressed in the brains of depressed suicide victims [Schmauss C (2003)Serotonin 2C receptors: suicide, serotonin, and runaway RNA editing.Neuroscientist 9:237-242. Iwamoto K, Kato T (2003). RNA editing ofserotonin 2C receptor in human postmortem brains of major mentaldisorders. Neurosci. Lett. 346:169-172] and in the learned helplessnessrats (a well established animal model of depression) [Iwamotoa K,Nakatanib N, Bundoa M, Yoshikawab T, Katoa T (2005). Altered RNA editingof serotonin 2C receptor in a rat model of depression. Neurosci. Res.53: 69-76] suggesting a link between 5-HT_(2C) function and depression.There are also implications of edited 5-HT_(2C) isoforms and spatialmemory [Du Y, Stasko M, Costa A C, Davissone M T, Gardiner K J (2007).Editing of the serotonin 2C receptor pre-mRNA Effects of the MorrisWater Maze. Gene 391:186-197]. In addition, fully edited isoforms of thehuman 5-HT_(2C) receptor display a striking reduction in sensitivity tolysergic acid diethylamide (LSD) and to atypical antipsychotic drugsclozapine and loxapine, suggesting a possible role of the receptor inthe etiology and pharmacology of schizophrenia [Niswender C M,Herrick-Davis K, Dilley G E, Meltzer H Y, Overholser J C, Stockmeier CA, Emeson R B, Sanders-Bush E (2001). RNA Editing of the Human Serotonin5-HT_(2C) Receptor: Alterations in Suicide and Implications forSerotonergic Pharmacotherapy. Neuropsychopharm. 24:478-491].

Recently, the availability of potent and selective 5-HT_(2C) receptoragonists made it possible to directly investigate the effects of5-HT_(2C) agonists and their therapeutic potential. Thus recent studiesdemonstrated that selective 5-HT_(2C) agonists resulted in decreasedfood intake and body weight gain in normal and obese rats [Smith B M, etal. (2008). Discovery and structure-activity relationship of(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin),a selective serotonin 5-HT_(2C) receptor agonist for the treatment ofobesity. J Med Chem 51:305-313. Thomsen W J, Grottick A J, Menzaghi F,Reyes-Saldana H, Espitia S, Yuskin D, Whelan K, Martin M, Morgan M, ChenW, Al-Shama H, Smith B, Chalmers D, Behan D (2008) Lorcaserin, A NovelSelective Human 5-HT_(2C) Agonist: In Vitro and In Vivo PharmacologicalCharacterization. J Pharmacol Exp Ther. 325:577-587. Rosenzweig-LipsonS, Zhang J, Mazandarani H, Harrison B L, Sabb A, Sabalski J, Stack G,Welmaker G, Barrett J E, Dunlop J (2006) Antiobesity-like effects of the5-HT_(2C) receptor agonist WAY-161503. Brain Res. 1073-1074:240-251.Dunlop J, Sabb A L, Mazandarani H, Zhang J, Kalgaonker S, Shukhina E,Sukoff S, Vogel R L, Stack G, Schechter L, Harrison B L,Rosenzweig-Lipson S (2005). WAY-163909 [97bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole],a novel 5-hydroxytryptamine 2C receptor—selective agonist with anorecticactivity. J Pharmacol Exp Ther. 313:862-869.].

Furthermore, selective 5-HT_(2C) receptor agonists produceantidepressant effects in animal models of depression comparable tothose of SSRIs but with a much faster onset of action and a therapeuticwindow that avoids antidepressant-induced sexual dysfunction. Theseagonists were also effective in animal models of compulsive behaviorsuch as scheduled induced polydipsia and they also exhibited decreasedhyperactivity and aggression in rodents [Rosenzweig-Lipson S, Sabb A,Stack G, Mitchell P, Lucki I, Malberg J E, Grauer S, Brennan J, Cryan JF, Sukoff Rizzo S J, Dunlop J, Barrett J E, Marquis KL (2007)Antidepressant-like effects of the novel, selective, 5-HT_(2C) receptoragonist WAY-163909 in rodents. Psychopharmacology (Berlin) 192:159-170.Rosenzweig-Lipson S, Dunlop J, Marquis K L (2007) 5-HT_(2C) receptoragonists as an innovative approach for psychiatric disorders. Drug newsPerspect, 20: 565-571. Cryan, J F, Lucki I (2000). Antidepressant-likebehavioral effects mediated by 5-Hydroxytryptamine 2C receptors. J.Pharm. Exp. Ther. 295:1120-1126.].

Acute or chronic administration of 5-HT_(2C) agonists decreases thefiring rate of ventral tegmental area dopamine neurons but not that ofsubstantia nigra. In addition 5-HT_(2C) agonists reduce dopamine levelsin the nucleus accumbens but not in the striatum (the region of thebrain mostly associated with extrapyramidal side effects) [Di Matteo,V., Di Giovanni, G., Di Mascio, M., & Esposito, E. (1999). SB 242084, aselective serotonin 2C receptor antagonist, increases dopaminergictransmission in the mesolimbic system. Neuropharmacology 38, 1195-1205.Di Giovanni, G., Di Matteo, V., Di Mascio, M., & Esposito, E. (2000).Preferential modulation of mesolimbic vs. nigrostriatal dopaminergicfunction by serotonin2C/2B receptor agonists: a combined in vivoelectrophysiological and microdialysis study. Synapse 35, 53-61. MarquisK L, Sabb A L, Logue S F, Brennan J A, Piesla M J, Comery T A, Grauer SM, Ashby C R, Jr., Nguyen H Q, Dawson L A, Barrett J E, Stack G, MeltzerH Y, Harrison B L, Rosenzweig-Lipson S (2007) WAY-163909[(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A novel 5-hydroxytryptamine 2C receptor-selective agonistwith preclinical antipsychotic-like activity. J Pharmacol Exp Ther320:486-496.]. Therefore it is expected that 5-HT_(2C) receptor agonistswill selectively decrease mesolimibic dopamine levels without affectingthe nigrostriatal pathway thus avoiding the EPS side effects of typicalantipsychotics. Several 5-HT_(2C) receptor agonists have shownantipsychotic activity in animal models of schizophrenia without EPSbased on the lack of effect in catalepsy [Marquis K L, Sabb A L, Logue SF, Brennan J A, Piesla M J, Comery T A, Grauer S M, Ashby C R, Jr.,Nguyen H Q, Dawson L A, Barrett J E, Stack G, Meltzer H Y, Harrison B L,Rosenzweig-Lipson S (2007) WAY-163909[(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A novel 5-hydroxytryptamine 2C receptor-selective agonistwith preclinical antipsychotic-like activity. J Pharmacol Exp Ther320:486-496. Siuciak J A, Chapin D S, McCarthy S A, Guanowsky V, BrownJ, Chiang P, Marala R, Patterson T, Seymour Pa., Swick A, Iredale Pa.(2007) CP-809, 101, a selective 5-HT_(2C) agonist, shows activity inanimal models of antipsychotic activity. Neuropharmacology 52:279-290].The antipsychotic activity of 5-HT_(2C) receptor agonists without EPScoupled with their beneficial effects in mood disorders and cognitionand their antiobesity like effects render 5-HT_(2C) receptor agonists asunique agents to treat schizophrenia [Rosenzweig-Lipson S, Dunlop J,Marquis KL (2007) 5-HT_(2C) receptor agonists as an innovative approachfor psychiatric disorders. Drug news Perspect, 20: 565-571. Dunlop J,Marquis K L, Lim H K, Leung L, Kao J, Cheesman C, Rosenzweig-Lipson S(2006). Pharmacological profile of the 5-HT_(2C) receptor agonistWAY-163909; therapeutic potential in multiple indications. CNS Dug Rev.12:167-177.].

In addition 5-HT_(2C) modulation has been implicated in epilepsy [IsaacM (2005). Serotonergic 5-HT_(2C) receptors as a potential therapeutictarget for the antiepileptic drugs. Curr. Topics Med. Chem. 5:59:67],psoriasis [Thorslund K, Nordlind K (2007). Serotonergic drugs-a possiblerole in the treatment of psoriasis? Drug News Perspect 20:521-525],Parkinson's disease and related motor disorders [Esposito E, Di Mateo V,Pierucci M, Benigno A, Di Giavanni, G (2007). Role of central 5-HT_(2C)receptor in the control of basal ganglia functions. The Basal GangliaPathophysiology: Recent Advances 97-127], behavioral deficits [Barr A M,Lahmann-Masten V, Paulus M, Gainetdinov R P, Caron M G, Geyer M A(2004). The selective serotonin-2A receptor antagonist M100907 reversesbehavioral deficits in dopamine transporter knockout mice.Neuropsychopharmacology 29:221-228], anxiety [Dekeyne A, Mannoury laCour C, Gobert A, Brocco M, Lejuene F, Serres F, Sharp T, Daszuta A,Soumier A, Papp M, Rivet J M, Flik G, Cremers T I, Muller O, Lavielle G,Millan M J (2208). 532006, a novel 5-HT_(2C) receptor antagonistsdisplaying broad-based antidepressant and anxiolytic properties inrodent models. Psychopharmacology 199:549-568. Nunes-de-Souza V,Nunes-de-Souza R L, Rodgers R J, Canto-de-Souza A (2008). 5-HT2 receptoractivation in the midbrain periaqueductal grey (PAG) reducesanxiety-like behavior in mice. Behav. Brain Res. 187:72-79.], migraine[Leone M, Rigamonti A, D'Amico D, Grazzi L, Usai S, Bussone G (2001).The serotonergic system in migraine. Journal of Headache and Pain2(Suppl. 1):S43-S46], Alzheimer's disease [Arjona A A, Pooler A M, Lee RK, Wurtman R J (2002). Effect of a 5-HT_(2C) serotonin agonist,dexnorfenfluramine, on amyloid precursor protein metabolism in guineapigs. Brain Res. %1:135-140], pain and spinal cord injury [Nakae A,Nakai K, Tanaka T, Hagihira S, Shibata M, Ueda K, Masimo T (2008). Therole of RNA editing of the serotonin 2C receptor in a rat model oforo-facial neuropathic pain. The European Journal of Neuroscience27:2373-2379. Nakae A, Nakai K, Tanaka T, Takashina M, Hagihira S,Shibata M, Ueda K, Mashimo T (2008). Serotonin 2C receptor mRNA editingin neuropathic pain model. Neurosci. Res. 60:228-231. Kao T, Shumsky JS, Jacob-Vadakot S, Timothy H B, Murray M, Moxon, K A (2006). Role ofthe 5-HT_(2C) receptor in improving weight-supported stepping in adultrats spinalized as neonates. Brain Res. 1112:159-168.], sexualdysfunction [Motofei I G (2008). A dual physiological character forsexual function: the role of serotonergic receptors. BJU International101:531-534. Shimada I, Maeno K, Kondoh Y, Kaku H, Sugasawa K Kimura Y,Hatanaka K; Naitou Y, Wanibuchi F, Sakamoto S; Tsukamoto S (2008).Synthesis and structure-activity relationships of a series ofbenzazepine derivatives as 5-HT_(2C) receptor agonists. Bioorg. Med.Chem. 16:3309-3320], smoking cessation [Fletcher P J, Le A D, Higgins GA (2008). Serotonin receptors as potential targets for modulation ofnicotine use and dependence. Progress Brain Res. 172:361-83], substancedependence [Bubar M J, Cunningham K A (2008). Prospects for serotonin5-HT2R pharmacotherapy in psychostimulant abuse. Progress Brain Res.172:319-46], and ocular hypertension [Sharif N A, McLaughlin M A, KellyC R (2006). AL-34662: a potent, selective, and efficacious ocularhypotensive serotonin-2 receptor agonist. J Ocul Pharmacol Ther.23:1-13].

Further, 5HT modulation can be useful in the treatment of pain, bothneuropathic and nociceptive pain, see for example U.S. Patentapplication publication US2007/0225277. Obata, Hideaki; Ito, Naomi;Sasaki, Masayuki; Saito, Shigeru; Goto, Fumio. Possible involvement ofspinal noradrenergic mechanisms in the antiallodynic effect ofintrathecally administered 5-HT2C receptor agonists in the rats withperipheral nerve injury. European Journal of Pharmacology (2007),567(1-2), 89-94. Serotonin2C receptor mRNA editing in neuropathic painmodel. Nakae, Aya; Nakai, Kunihiro; Tanaka, Tatsuya; Takashina, Masaki;Hagihira, Satoshi; Shibata, Masahiko; Ueda, Koichi; Mashimo, Takashi.Department of Anesthesiology & Intensive Care Medicine, Graduate Schoolof Medicine, Osaka University, Neuroscience Research (Amsterdam,Netherlands) (2008), 60(2), 228-231. Antiallodynic effects ofintrathecally administered 5-HT2C receptor agonists in rats with nerveinjury. Obata, Hideaki; Saito, Shigeru; Sakurazawa, Shinobu; Sasaki,Masayuki; Usui, Tadashi; Goto, Fumio Department of Anesthesiology, GunmaUniversity Graduate School of Medicine, Maebashi, Gunma, Japan. Pain(2004), 108(1-2), 163-169. Influence of 5,7-dihydroxytryptamine(5,7-DHT) on the antinociceptive effect of serotonin (5-HT) 5-HT2Creceptor agonist in male and female rats. Brus, Ryszard; Kasperska,Alicja; Oswiecimska, Joanna; Szkilnik, Ryszard. Department ofPharmacology, Silesian Medical University, Zabrze, Pol. Medical ScienceMonitor (1997), 3(5), 654-656.

Modulation of 5HT2 receptors may be beneficial in the treatment ofconditions related to bladder function, in particular, urinaryincontinence. [Discovery of a novel azepine series of potent andselective 5-HT2C agonists as potential treatments for urinaryincontinence. Brennan, Paul E.; Whitlock, Gavin A.; Ho, Danny K. H.;Conlon, Kelly; McMurray, Gordon. Bioorganic & Medicinal ChemistryLetters (2009), 19(17), 4999-5003. Investigation of the role of 5-HT2receptor subtypes in the control of the bladder and the urethra in theanesthetized female rat. Mbaki, Y.; Ramage, A. G. Department ofPharmacology, University College London, London, UK. British Journal ofPharmacology (2008), 155(3), 343-356.] In particular, compounds withagonist activity at 5-HT_(2C) have been shown to be useful in treatingurinary incontinence, see for example U.S. Patent applicationpublications US2008/0146583 and US 2007/0225274.

Further pre-clinical data suggest that 5-HT_(2C) agonists could beuseful for the treatment of a number of psychiatric diseases, includingschizophrenia, bipolar disorders, depression/anxiety, substance usedisorders and especially disorders like neuropsychiatric symptoms inAlzheimer's disease: Aggression, psychosis/agitation represent key unmetmedical needs. Clinical (Shen J H Q et al., A 6-week randomized,double-blind, placebo-controlled, comparator referenced trial ofvabicaserin in acute schizophrenia. Journal of Psychiatric Research 53(2014) 14-22; Liu J et al., Prediction of Efficacy of Vabicaserin, a5-HT_(2C) Agonist, for the Treatment of Schizophrenia Using aQuantitative Systems Pharmacology Model. CPT Pharmacometrics Syst.Pharmacol. (2014) 3, ell 1;) and preclinical data (Dunlop J et al.,Characterization of Vabicaserin (SCA-136), a Selective5-Hydroxytryptamine 2C Receptor Agonist. J Pharmacol Exp Ther (2011)337, 673-80; Siuciak J et al., CP-809, 101, a selective 5-HT_(2C)agonist, shows activity in animal models of antipsychotic activity.Neuropharmacology 52 (2007) 279-290; Mosienko V et al., Exaggeratedaggression and decreased anxiety in mice deficient in brain serotonin.Transl Psychiatry (2012) 2, e122; Del Guidice T et al., Stimulation of5-HT_(2C) Receptors Improves Cognitive Deficits Induced by HumanTryptophan Hydroxylase2 Loss of Function Mutation.Neuropsychopharmacology (2014) 39, 1125-1134; Rosenzweig-Lipson et al.,Antidepressant-like effects of the novel, selective, 5-HT_(2C) receptoragonist WAY-163909 in rodents. Psychopharmacology (2007) 192:159-170)suggest 5-HT_(2C) receptor stimulation to result in therapeutic efficacyin aggression, psychosis agitation and moderate pro-cognitive effects(Del Guidice T et al., Stimulation of 5-HT_(2C) Receptors ImprovesCognitive Deficits Induced by Human Tryptophan Hydroxylase2 Loss ofFunction Mutation. Neuropsychopharmacology (2014) 39, 1125-1134; SiuciakJ et al., CP-809, 101, a selective 5-HT_(2C) agonist, shows activity inanimal models of antipsychotic activity. Neuropharmacology 52 (2007)279-290).

In the use and the method of the invention, an effective quantity of oneor more compounds, as a rule formulated in accordance withpharmaceutical and veterinary practice, is administered to theindividual to be treated, preferably a mammal, in particular a humanbeing, productive animal or domestic animal. Whether such a treatment isindicated, and in which form it is to take place, depends on theindividual case and is subject to medical assessment (diagnosis) whichtakes into consideration signs, symptoms and/or malfunctions which arepresent, the risks of developing particular signs, symptoms and/ormalfunctions, and other factors.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of the present invention can be varied so as to obtain anamount of the active compound(s) that is effective to achieve thedesired therapeutic response for a particular subject (e.g., a mammal,preferably, a human (patient)), compositions and mode of administration.The selected dosage level will depend upon the activity of theparticular compound, the route of administration, the severity of thecondition being treated and the condition and prior medical history ofthe patient being treated. However, it is within the skill of the art tostart doses of the compound at levels lower than required to achieve thedesired therapeutic effect and to gradually increase the dosage untilthe desired effect is achieved.

Compounds of the present invention can also be administered to a subjectas a pharmaceutical composition comprising the compounds of interest incombination with at least one pharmaceutically acceptable carriers. Thephrase “therapeutically effective amount” of the compound of the presentinvention means a sufficient amount of the compound to treat disorders,at a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa subject (namely, a mammal, such as a human) ranges from about 0.01mg/kg body weight to about 100 mg/kg body weight. More preferable dosescan be in the range of from about 0.01 mg/kg body weight to about 30mg/kg body weight. If desired, the effective daily dose can be dividedinto multiple doses for purposes of administration. Consequently, singledose compositions may contain such amounts or submultiples thereof tomake up the daily dose.

In one aspect, the present invention provides pharmaceuticalcompositions. The pharmaceutical compositions of the present inventioncomprise the compounds of the present invention or an N-oxide, atautomeric form, a stereoisomer or a pharmaceutically acceptable salt orsolvate thereof. The pharmaceutical compositions of the presentinvention comprise compounds of the present invention that can beformulated together with at least one non-toxic pharmaceuticallyacceptable carrier.

In yet another embodiment, the present invention provides apharmaceutical composition comprising compounds of the present inventionor an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarriers, alone or in combination with one or more compounds that arenot the compounds of the present invention. Examples of one or morecompounds that can be combined with the compounds of the presentinvention in pharmaceutical compositions, include, but are not limitedto, one or more cognitive enhancing drugs.

The pharmaceutical compositions of this present invention can beadministered to a subject (e.g., a mammal, such as a human) orally,rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments or drops),bucally or as an oral or nasal spray. The term “parenterally” as usedherein, refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of the present invention for parenteralinjection comprise pharmaceutically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions as well assterile powders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of the presentinvention include powders, sprays, ointments and inhalants. The activecompound may be mixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives, buffers or propellantswhich may be required. Ophthalmic formulations, eye ointments, powdersand solutions are also contemplated as being within the scope of thisinvention.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M.

Berge et al. describe pharmaceutically acceptable salts in detail in (J.Pharmaceutical Sciences, 1977, 66: 1 et seq.). The salts can be preparedin situ during the final isolation and purification of the compounds ofthe invention or separately by reacting a free base function with asuitable organic acid. Representative acid addition salts include, butare not limited to acetate, adipate, alginate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, malate,maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as, but not limited to, methyl, ethyl, propyl,and butyl chlorides, bromides and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides suchas, but not limited to, decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; arylalkyl halides like benzyl and phenethylbromides and others. Water or oil-soluble or dispersible products arethereby obtained. Examples of acids which can be employed to formpharmaceutically acceptable acid addition salts include such inorganicacids as hydrochloric acid, hydrobromic acid, sulfuric acid, andphosphoric acid and such organic acids as acetic acid, fumaric acid,maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citricacid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium,triethylammonium, diethylammonium, ethylammonium and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

The compounds of the present invention can exist in unsolvated as wellas solvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

The following examples serve to explain the invention without limitingit.

EXAMPLES

The compounds were either characterized via proton-NMR ind₆-dimethylsulfoxide, d-chloroform or d₄-methanol on a 400 MHz, 500 MHzor 600 MHz NMR instrument (Bruker AVANCE), or by ¹³C-NMR at 125 MHz, orby mass spectrometry, generally recorded via HPLC-MS in a fast gradienton C18-material (electrospray-ionisation (ESI) mode).

The magnetic nuclear resonance spectral properties (NMR) refer to thechemical shifts (δ) expressed in parts per million (ppm). The relativearea of the shifts in the ¹H-NMR spectrum corresponds to the number ofhydrogen atoms for a particular functional type in the molecule. Thenature of the shift, as regards multiplicity, is indicated as singlet(s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet(t), broad triplet (t br.), quartet (q), quintet (quint.), multiplet(m), doublet of doublets (dd), doublet of doublets of doublets (ddd)etc.

Enantiomers were Separated/Purified by Chiral Supercritical FluidChromatography (SFC) (Method A).

Method A: Analytical Separation Method:

Instrument: Thar analytical SFCColumn: Chiralpak AD-3 3 μm, 0.46 cm id×10 cm LMobile phase: A for SFC CO₂ and B for EtOH (0.05% IPAm)Gradient: B in A from 10% to 40% in 5 minutesFlow rate: 4.0 mL/min

Wavelength: 220 nm System Back Pressure: 100 bar Preparative SeparationMethod: Instrument: Thar SFC Pre-80

Column: Chiralpak AD-H 5 μm, 3.0 cm id×25 cm LMobile phase: A for SFC CO₂ and B EtOH (0.05% NH₄OH)

Gradient: A:B=78:22

Flow rate: 60 mL/min

Wavelength: 220 nm System Back Pressure: 100 bar

Sample preparation: dissolved in Methanol, 14 mg/mLInjection: 1.0 ml per injection.

IPAm: Isopropylamine Preparative HPLC was Carried Out Under FollowingConditions: Method A:

Instrument: Shimadzu LC-20AP preparative HPLC

Column: Luna(2) C18 250*50 mm i.d. 10 u

Mobile phase: A for H₂O (0.075% TFA) and B for MeCNGradient: B from 12% to 42% in 20 minFlow rate: 80 ml/min

Wavelength: 220 & 254 nm

Injection amount: 0.65 g per injection

Method B:

Instrument: Gilson 281 semi-preparative HPLC systemMobile phase: A for H₂O (0.075% TFA) and B for MeCN

Column: Luna C18 100*30, Sum, 100A

Flow rate: 25 ml/minMonitor wavelength: 220& 254 nm

Gradient:

Time B % 0.00 80 12.0 100 12.2 100 14.2 100 14.4 80 16.0 80

Method C C.1 Analytical SFC

Analytical samples were run on an Agilent 1260 Infinity Hybrid SFCSystem, controlled by Agilent OpenLab CDS ChemStation Edition. Thesystem consists of an injector, a heated column compartment including aswitch for 6 columns, a CO₂-booster pump, a binary pump module for CO₂and modifier flow and an UV-detector. The backpressure regulator was setto 160 bars and heated to 60° C. If not stated otherwise, the columnswere 100 mm in length, 4.6 mm in diameter and packed with 5 μm material.They were kept at room temperature during analysis. As mobile phase, amixture of liquefied CO₂ and organic modifier with additive was used asindicated for each sample. The flow rate was kept at 3.5 mL/min.

C.2 Preparative SFC

Preparative separations were carried out on a Waters Prep 100q SFCSystem, controlled by Waters MassLynx Software. The system consists ofan open bed injector/collector, a heated column compartment including aswitch for 6 columns, a CO₂-booster pump, a pump module for modifierflow and an UV-detector. To enable quantitative collection, the gasliquid separator was driven with a make-up flow of 30 mL/min Methanol.The backpressure regulator was set to 120 bar and heated to 60° C. Ifnot stated otherwise, the columns were 250 mm in length, 20 mm indiameter and packed with 5 μm material. They were kept at 30° C. duringthe separation. As mobile phase, a mixture of liquefied CO₂ and organicmodifier with additive was used as indicated for each sample. The flowrate was kept at 100 g/min.

LCMS Method:

LC/MS (The gradient was 1-90% B in 3.4 min, 90-100% B in 0.45 min,100-1% B in 0.01 min, and then held at 1% B for 0.65 min (0.8 mL/minflow rate). Mobile phase A was 0.0375% TFA in water, mobile phase B was0.018% TFA in MeCN. The column used for the chromatography was a 2.1×50mm Venusil XBP-C18 column (5 μm particles). Detection methods are diodearray (DAD) and evaporative light scattering (ELSD) detection as well aspositive/negative electrospray ionization).

ABBREVIATIONS

h hour(s)min minute(s)r.t. room temperature (20-25° C.)PE petroleum etherEtOH ethanolMeOH methanolDCM dichloromethaneDCE dichloroethaneTHF tetrahydrofuran

DMF N,N-dimethylformamide

MeCN acetonitrileEtOAc ethyl acetateTFA trifluoroacetic acidDIPEA diisopropylethyl amineX-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

I. Preparation Examples Example 18-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(compound Ia.1 wherein R⁶ is cyclopropyl and R^(4a), R^(4b), R^(5a),R^(5b) and R^(7a) are hydrogen) 1.1 4-Cyclopropylquinoline

A mixture of 4-bromoquinoline (18 g, 87 mmol), cyclopropylboronic acid(29.7 g, 346 mmol), tricyclohexylphosphine (4.85 g, 17.3 mmol), K₃PO₄(73.5 g, 346 mmol) and PdOAc₂ (1.942 g, 8.65 mmol) in toluene (200 mL)and water (20 mL) was stirred for 16 h at 100° C. under N₂. Theresulting mixture was concentrated under reduced pressure and theresidue was purified by column chromatography on silica gel(PE:EtOAc=10:1) to give the title compound (10 g, yield 61.2%).

¹H NMR (400 MHz; CDCl₃): δ 9.00 (d, J=4.4 Hz, 1H), 8.55 (d, J=8.4 Hz,1H), 8.34 (d, J=8.4 Hz, 1H), 7.93 (t, J=8.0 Hz, 1H), 7.80 (t, J=8.0 Hz,1H), 7.24 (d, J=4.4 Hz, 1H), 2.68-2.61 (m, 1H), 1.42-1.36 (m, 2H),1.09-1.05 (m, 2H).

1.2 1-(2-Amino-2-oxoethyl)-4-cyclopropylquinolin-1-ium bromide

A mixture of 4-cyclopropylquinoline from step 1.1 (9 g, 53.2 mmol) and2-bromoacetamide (14.67 g, 106 mmol) in EtOH (100 mL) was stirred at 90°C. for 16 h. After cooling to 20° C., the mixture was filtered, and theresidue was dried in high vacuum to give the title compound (9 g, yield55.1%).

¹H NMR (400 MHz; d₆-DMSO): δ 9.24 (d, J=6.0 Hz, 1H), 8.88 (d, J=8.0 Hz,1H), 8.24-8.13 (m, 3H), 8.03 (t, J=8.0 Hz, 1H), 7.76 (s, 1H), 7.69 (d,J=6.4 Hz, 1H), 5.71 (s, 2H), 3.11-3.05 (m, 1H), 1.55-1.52 (m, 2H),1.34-1.31 (m, 2H).

1.3 2-(4-Cyclopropyl-2H-quinolin-1-yl)acetamide

To a solution of 1-(2-amino-2-oxoethyl)-4-cyclopropylquinolin-1-iumbromide from step 1.2 (9 g, 29.3 mmol) in MeOH (200 mL), NaBH₄ (11.08 g,293 mmol) was added in portions at 0° C., and then the mixture wasstirred at 60° C. for 2 hours. After cooled to 20° C., water (50 mL) wasadded, and the reaction mixture was extracted with DCM (50 mL×2), andthe organic phase was dried with Na₂SO₄, concentrated under reducedpressure to give crude title compound (5 g, 74.8% yield), which was useddirectly in the next step.

LCMS (ESI⁺): m/z 228.9 (M+H)⁺, RT: 1.03 min.

1.4 2-(4-Cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)acetamide

To a solution of 2-(4-cyclopropyl-2H-quinolin-1-yl)acetamide from step1.3 (5 g, 21.9 mmol) in MeOH (100 mL), Raney Ni (1.286 g, 21.9 mmol) wasadded under Ar, and the reaction mixture was stirred for 12 h at 20° C.under H₂ (15 psi of pressure). Then the mixture was filtered, thefiltrate was concentrated under reduced pressure and the residue waspurified by preparative HPLC (method A) to give the title compound (1.8g, yield 35.7%)

¹H NMR (400 MHz; CDCl₃): δ 7.18 (d, J=7.2 Hz, 1H), 6.93 (t, J=7.2 Hz,1H), 6.57 (t, J=7.6 Hz, 1H), 6.45 (s, 1H), 6.25 (d, J=8.4 Hz, 1H), 6.25(s, 1H), 3.65 (s, 2H), 3.30-3.27 (m, 1H), 3.16-3.14 (m, 1H), 1.96-1.81(m, 3H), 0.73-0.70 (m, 1H), 0.53-0.52 (m, 1H), 0.33-0.32 (m, 1H),0.27-0.23 (m, 1H), 0.05-0.02 (m, 1H)

1.5 2-(4-Cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 2-(4-cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)acetamidefrom step 1.4 (1.8 g, 7.82 mmol) in THF (50 mL), a solution of BH₃.THF(15.6 mL, 15.63 mmol) was added at 0° C., and the reaction solution wasstirred for 12 h at 70° C. After cooling to 20° C., MeOH (20 mL) wasadded dropwise at 0° C. The reaction solution was stirred for 30 minutesat 20° C. and then concentrated under reduced pressure to give aresidue, which was purified by preparative HPLC (method A) to give thetitle compound (900 mg, yield 53.2%)

¹H NMR (400 MHz; CDCl₃): δ 7.81 (s, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.93(t, J=7.6 Hz, 1H), 6.57-6.49 (m, 2H), 3.41-3.38 (m, 3H), 3.33-3.19 (m,1H), 3.08-3.07 (m, 1H), 2.99-2.96 (m, 2H), 1.89-1.86 (m, 1H), 1.80-1.73(m, 2H), 0.71-0.68 (m, 1H), 0.53-0.52 (m, 1H), 0.35-0.32 (m, 1H),0.25-0.22 (m, 1H), 0.05-0.02 (m, 1H)

1.68-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

To a solution of2-(4-cyclopropyl-3,4-dihydroquinolin-1(211)-yl)ethanamine from step 1.5(900 mg, 4.16 mmol) and 37% formaldehyde solution (0.93 mL, 12.48 mmol)in EtOH (15 mL), TFA (0.962 mL, 12.48 mmol) was added at 0° C., and thereaction mixture was stirred for 2 h at 80° C. Then the reactionsolution was concentrated under reduced pressure and the residue waspurified by preparative HPLC (method A) to give the title compound (500mg, yield 52.6%).

LCMS (ESI⁺): m/z 229.1 (M+H)⁺, RT: 0.979 min.

1.7 Racemic resolution of8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolineto(S)-8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolineand(R)-8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(500 mg, 2.19 mmol) was separated by chiral SFC (method A) to giveenantiomer 1.A (107.7 mg, yield 21.5%), and enantiomer 1.B (125.6 mg,yield 25.1%).

Enantiomer 1.A was collected from 7.0 min to 9.6 min; and enantiomer 1.Bwas collected from 10.2 min to 12.8 min.

¹H NMR of enantiomer 1.A (400 MHz; CD₃OD): δ 7.33 (d, J=7.6 Hz, 1H),7.01 (d, J=7.6 Hz, 1H), 6.78 (t, J=7.6 Hz, 1H), 3.85 (s, 2H), 3.43-3.41(m, 1H), 3.29-3.26 (m, 1H), 3.14-3.12 (m, 2H), 3.06-3.04 (m, 2H),2.06-1.96 (m, 2H), 1.86-1.84 (m, 1H), 0.87-0.85 (m, 1H), 0.71-0.69 (m,1H), 0.51-0.46 (m, 2H), 0.25-0.24 (m, 1H)

LCMS (ESI⁺) of enantiomer A: m/z 229.1 (M+H)⁺, RT: 2.455 min.

¹H NMR of enantiomer 1.B (400 MHz; CD₃OD): δ 7.45 (d, J=7.6 Hz, 1H),7.12 (d, J=7.2 Hz, 1H), 6.87 (t, J=7.6 Hz, 1H), 4.16 (s, 2H), 3.48-3.43(m, 1H), 3.32-3.30 (m, 5H), 2.07-1.98 (m, 2H), 1.87-1.86 (m, 1H),0.87-0.85 (m, 1H), 0.71-0.69 (m, 1H), 0.51-0.46 (m, 2H), 0.26-0.25 (m,1H)

LCMS (ESI⁺) of enantiomer B: m/z 229.1 (M+H)⁺, RT: 2.460 min.

Example 28-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(compound Ia.1 wherein R⁶ is cyclobutyl and R^(4a), R^(4b), R^(5a),R^(5b) and R^(7a) are hydrogen) 2.1 4-Cyclobutylquinoline

A mixture of 4-bromoquinoline (600 mg, 2.88 mmol),di(adamantan-1-yl)(butyl)-phosphine (70 mg, 0.195 mmol), Pd(OAc)₂ (26mg, 0.116 mmol), potassium cyclobutyltrifluoroborate (600 mg, 3.70 mmol)and Cs₂CO₃ (2819 mg, 8.65 mmol) in toluene (11 mL) and water (1.1 mL)was heated at 100° C. for 72 h under N₂. After cooling to 25° C., water(20 mL) was added, and the mixture was extracted with EtOAc (30 mL×2).The organic phase was dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue, which was purified by preparativeHPLC (method A) to give the title compound (300 mg, 56.8% yield) asyellow oil.

¹H NMR (400 MHz; CDCl₃): δ 8.85 (s, 1H), 8.10 (d, J=8.4 Hz, 1H),7.93-7.91 (m, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.54-7.50 (m, 1H), 7.26 (d,J=4.9 Hz, 1H), 4.19-4.10 (m, 1H), 2.59-2.51 (m, 2H), 2.36-2.26 (m, 2H),2.24-2.13 (m, 1H), 1.97-1.90 (m, 1H)

2.2 1-Benzyl-4-cyclobutyl-quinolin-1-ium bromide

A mixture of 4-cyclobutylquinoline from step 2.1 (100 mg, 0.546 mmol)and (bromomethyl)benzene (747 mg, 4.37 mmol) in toluene (15 mL) wasstirred for 12 h at 80° C. After cooling, the resulting mixture wasfiltered and the residue was dried by high vacuum to give the titlecompound (50 mg, yield 13%), which was used in the next step withoutfurther purification.

2.3 1-Benzyl-4-cyclobutyl-1,2,3,4-tetrahydroquinoline

To a solution of 1-benzyl-4-cyclobutyl-quinolin-1-ium bromide from step2.2 (200 mg, 0.565 mmol) in MeOH (20 mL) was added NaBH₄ (320 mg, 8.47mmol) in portions at 25° C. and the reaction mixture was stirred for 3 hat 25° C. Then Raney nickel (128 mg, 2.179 mmol) was added at 25° C.under Ar, and the reaction solution was stirred for 2 h at 15 psipressure of H₂. The reaction mixture was filtered, the filtrate wasconcentrated under reduced pressure and the residue was purified bypreparative HPLC (method B) to give the title compound (100 mg, yield49.6%).

¹H NMR (400 MHz; CDCl₃): δ 7.26-7.14 (m, 5H), 6.93-6.89 (m, 2H),6.5-6.43 (m, 2H), 4.42 (t, J=4.9 Hz, 2H), 3.34-3.27 (m, 1H), 3.20-3.14(m, 1H), 2.63-2.58 (m, 1H), 2.47-2.37 (m, 1H), 2.01-1.83 (m, 4H),1.78-1.65 (m, 4H).

2.4 4-Cyclobutyl-1,2,3,4-tetrahydroquinoline

To a solution of 1-benzyl-4-cyclobutyl-1,2,3,4-tetrahydroquinoline fromstep 2.3 (195 mg, 0.703 mmol) in DCE (20 mL), 1-chloroethylcarbonochloridate (502 mg, 3.51 mmol) was added and the solution washeated to 80° C. for 12 h under N₂. After cooling to 20° C., MeOH (5 mL)was added and the resulting solution was heated to 80° C. for 3 h. Themixture was concentrated under reduced pressure and the residue waspurified by preparative HPLC (method A, however gradient: B from 5% to35% in 20 min and 0.25 g per injection) to give the title compound (126mg, yield 96%).

¹H NMR (400 MHz; CDCl₃): δ 6.92-6.88 (m, 2H), 6.52-6.48 (m, 1H), 6.30(d, J=8.0 Hz, 1H), 3.23-3.15 (m, 2H), 2.57-2.55 (m, 1H), 2.45-2.35 (m,1H), 2.0-1.9 (m, 3H), 1.73-1.66 (m, 6H).

2.5 2-(4-Cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)acetamide

To a solution of 4-cyclobutyl-1,2,3,4-tetrahydroquinoline from step 2.4(100 mg, 0.534 mmol) in DMF (20 mL), 2-iodoacetamide (593 mg, 3.2 mmol)was added and the solution was heated to 120° C. for 12 h under N₂.Water (20 mL) was added; the mixture was extracted with EtOAc (50 mL×2),and the organic phase was washed with HCl (20 mL, 1N) and brine, driedand concentrated under reduced pressure to give the title compound (100mg, yield 77%).

¹H NMR (400 MHz; CDCl₃): δ 7.04-6.96 (m, 2H), 6.64-6.60 (m, 1H), 6.438(d, J=8.0 Hz, 1H), 6.35 (s, 1H), 5.35 (s, 1H), 3.82-3.69 (m, 2H),3.29-3.25 (m, 1H), 3.17-3.14 (m, 1H), 2.62-2.59 (m, 1H), 2.39-2.35 (m,1H), 1.98-1.85 (m, 4H), 1.75-1.69 (m, 4H).

2.6 2-(4-Cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 2-(4-cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)acetamidefrom step 2.5 (150 mg, 0.614 mmol) in THF (20 mL), BH₃THF (5 mL, 5 mmol)was added, and the solution was heated to 80° C. for 12 h under N₂.After cooling to 25° C., MeOH (15 mL) was added dropwise, and thereaction solution mixture was stirred 30 minutes at 25° C. Then theresulting solution was concentrated under reduced pressure and theresidue was purified by preparative HPLC to give the title compound (100mg, yield 77%) (method B, however with following gradient:

Time B % 0.00 15 12.0 55 12.1 55 12.2 100  13.5 100  13.6 15 15.0  15)

¹H NMR (400 MHz; CD₃OD): δ 7.04-6.96 (m, 2H), 6.54 (d, J=8.0, 1H),6.58-6.54 (m, 1H), 3.59-3.51 (m, 2H), 3.21-3.11 (m, 3H), 3.82-3.69 (m,2H), 3.29-3.25 (m, 1H), 3.17-3.14 (m, 1H), 2.62-2.59 (m, 1H), 2.65-2.55(m, 1H), 2.5-2.4 (m, 1H), 2.06-1.76 (m, 9H).

2.78-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

To a solution of 2-(4-cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)ethanaminefrom step 2.6 (150 mg, 0.651 mmol) in EtOH (20 mL), formaldehyde (0.448mL, 6.51 mmol) and TFA (0.502 mL, 6.51 mmol) were added and the reactionmixture was heated at 80° C. for 2 h under N₂. The resulting solutionwas concentrated under reduced pressure and the residue was purified bypreparative HPLC to give the title compound (50 mg, yield 31.3%) (methodB, however with following gradient:

Time B % 0.00 10 12.0 50 12.1 50 12.2 100  13.5 100  13.6 10 15.0  10).

Example 38-(3-Methyloxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(compound Ia.1 wherein R⁶ is 3-methyloxetan-3-yl and R^(4a), R^(4b),R^(5a), R^(5b) and R^(7a) are hydrogen) 3.14-(3-Methyloxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one

In a 5 mL microwave vial containing 3-(3-methyloxetan-3-yl)-acrylic acidethyl ester (500 mg, 0.588 mmol, 1.00 eq), 2-aminophenyl boronic ester(805 mg, 1.18 mmol, 2.00 eq), potassium carbonate (812 mg, 1.18 mmol,2.00 eq) and [RhOH(COD)]₂ (67 mg, 0.029 mmol, 0.05 eq) was added 2% wt.TPGS-750-M solution in water (3 mL) (TPGS-750-M: a surfactant composedof a lipophilic α-tocopherol moiety and a hydrophilic PEG-750-M chain,joined by a succinic acid linker; forms spontaneously micelles upondissolution in water. From Sigma-Aldrich). The mixture was stirredvigorously at ambient temperature for 24 h. Then the reaction mixturewas extracted with ethyl acetate. The organic phase was dried overMgSO₄, filtrated and reduced under vacuum. The crude product waspurified by column chromatography on silica (eluent: 0-10% methanol indichloromethane) to yield the title compound (680 mg, 96% yield).

¹H NMR (500 MHz, CDCl₃) δ 9.15 (s, 1H), 7.22 (ddd, J=8.0, 6.5, 2.3 Hz,1H), 7.06-6.97 (m, 2H), 6.89-6.83 (m, 1H), 4.83 (d, J=5.9 Hz, 1H), 4.63(d, J=5.8 Hz, 1H), 4.41 (d, J=5.7 Hz, 1H), 4.29 (d, J=6.0 Hz, 1H), 3.57(dd, J=7.3, 4.7 Hz, 1H), 2.70 (dd, J=16.6, 7.3 Hz, 1H), 2.40 (dd,J=16.7, 4.7 Hz, 1H), 1.32 (s, 3H) ppm.

¹³C NMR (125 MHz, CDCl₃) δ 171.45, 137.42, 128.34, 128.06, 123.40,122.79, 116.16, 82.07, 81.95, 43.56, 42.78, 31.98, 19.10 ppm.

ESI-MS: m/z (%): 218.20 (100, [M+H]⁺).

3.2 4-(3-Methyloxetan-3-yl)-1,2,3,4-tetrahydroquinoline

640 mg of 4-(3-methyloxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one fromstep 3.1 (2.95 mmol, 1.00 eq) was dissolved in 2 mL of THF (anhydrous)and 5.89 mL of borane tetrahydrofurane complex (5.89 mmol, 1 M in THF,2.00 eq) was slowly added. The mixture was heated in a microwave at 60°C. for 20 min. Then the reaction mixture was quenched with HCl (1 M) andthe aqueous phase was extracted with ethyl acetate. Subsequently theorganic phase was extracted three times with HCl (1M) and NaOH (1M) wasadded to the aqueous phase until pH 10. This was then extracted withdichloromethane three times. The organic phase was dried over MgSO₄ andreduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-10% methanol in dichloromethane) toyield the title compound (345 mg, 52% yield).

ESI-MS: m/z (%): 204.10 (100, [M+H]⁺).

3.3 2-(4-(3-Methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 170 mg of4-(3-methyloxetan-3-yl)-1,2,3,4-tetrahydroquinoline from step 3.2 (0.836mmol, 1.00 eq), 2-iodoacetamide (309 mg, 1.67 mmol, 2.00 eq) and DIPEA(0.57 ml, 3.35 mmol, 4.00 eq) in DMF (3 mL) was heated in a microwave at130° C. for 2 h. Then NaOH (1M) was added and the mixture was extractedwith dichloromethane. The organic phase was dried over MgSO₄ and reducedunder vacuum. The crude product was purified by column chromatography onsilica (eluent: 0-10% methanol in dichloromethane) to yield the titlecompound (136 mg, 56% yield).

ESI-MS: m/z (%): 261.20 (100, [M+H]⁺).

3.4 2-(4-(3-Methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 50 mg of2-(4-(3-methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide fromstep 3.3 (0.192 mmol, 1.00 eq) in THF (2 ml) 0.768 mL of lithiumaluminium hydride (1 M in THF, 0.768 mmol, 4.00 eq) was slowly added at0° C. The mixture was stirred at 0° C. for 10 min and was then warmed upto r.t. and stirred for further 6 h at r.t. Then water (0.02 mL) wasadded followed by 10% aqueous NaOH (0.02 mL) and water (0.069 mL) again.Subsequently MgSO₄ was added, the mixture was filtrated and the solventwas evaporated. The crude product was purified by column chromatographyon silica (eluent: 0-10% methanol in dichloromethane) to yield the titlecompound (30 mg, 63% yield).

ESI-MS: m/z (%): 247.20 (100, [M+H]⁺).

3.58-(3-Methyloxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 30 mg of2-(4-(3-methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine fromstep 3.4 (0.122 mmol, 1.00 eq), formaldehyde (9.5 μL, 0.128 mmol, 1.10eq) and TFA (10.3 μL, 0.128 mmol, 1.10 eq) in ethanol (1 mL) was stirredat ambient temperature for 2 h. Then NaOH (1M) was added and the mixturewas extracted with dichloromethane. The organic phase was dried overMgSO₄ and reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-10% methanol in dichloromethane) toyield the title compound (16 mg, 51% yield).

¹H NMR (600 MHz, CDCl₃) δ 6.98 (d, 1H), 6.74 (t, J=7.5 Hz, 1H), 6.44 (d,J=7.8, 1.3 Hz, 1H), 4.97 (d, J=5.4 Hz, 1H), 4.77 (d, J=5.5 Hz, 1H), 4.50(dd, J=5.4, 0.8 Hz, 1H), 4.31 (dd, J=5.5, 0.8 Hz, 1H), 3.96 (d, J=14.3Hz, 1H), 3.84 (d, J=14.3 Hz, 1H), 3.38 (dd, J=10.6, 5.5 Hz, 1H),3.26-3.22 (m, 2H), 3.13-3.03 (m, 3H), 1.70-1.62 (m, 1H), 1.62-1.52 (m,1H), 1.28 (s, 3H).

ESI-MS: m/z (%): 259.20 (100, [M+H]⁺).

Example 48-(2,2-Difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(compound Ia.1 wherein R⁶ is 2,2-difluorocyclopropyl and R^(4a), R^(4b),R^(5a), R^(5b) and R^(7a) are hydrogen) 4.14-(2,2-Difluorocyclopropyl)-3,4-dihydroquinolin-2(1H)-one

A mixture of 1.26 g of (2,2-difluorocyclopropyl)-acrylic acid ethylester (7.16 mmol, 1.00 eq), 1.86 g of 2-aminophenyl boronic ester (13.6mmol, 1.90 eq), 1.60 g of potassium tert-butoxide (14.3 mmol, 2.00 eq)and 163 mg of [RhOH(COD)]₂ (0.358 mmol, 0.05 eq) in dioxane (10 mL) washeated in the microwave at 145° C. for 1 h. Then water and 1M HCl wereadded and the reaction mixture was extracted with ethyl acetate. Theorganic phase was dried over MgSO₄, filtrated and reduced under vacuum.The crude product was purified by column chromatography on silica(eluent: 0-10% methanol in dichloromethane) to yield the title product(44%, 3.17 mmol).

ESI-MS: m/z (%): 224.10 (100, [M+H]⁺).

4.2 4-(2,2-Difluorocyclopropyl)-1,2,3,4-tetrahydroquinoline

885 mg of 4-(2,2-difluorocyclopropyl)-3,4-dihydroquinolin-2(1H)-one(3.96 mmol, 1.00 eq) from step 4.1 was dissolved in 10 mL of THF (dry)and 5.95 mL of borane tetrahydrofurane complex (1 M in THF, 3.00 eq)were slowly added. The mixture was heated in a microwave at 90° C. for 2h. Then the reaction mixture was quenched with HCl (1 M) and the aqueousphase was extracted with ethyl acetate. The organic phase was extractedthree times with HCl (1M) and to the aqueous phase was added NaOH (1M)until pH 10 and was then extracted with dichloromethane three times. Theorganic phase was dried over MgSO₄ and reduced under vacuum. The crudeproduct was purified by column chromatography on silica (eluent: 0-10%methanol in dichloromethane) to yield the desired product (19%, 0.765mmol).

ESI-MS: m/z (%): 210.15 (100, [M+H]⁺).

4.32-(4-(2,2-Difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 180 mg of4-(2,2-difluorocyclopropyl)-1,2,3,4-tetrahydroquinoline (0.860 mmol,1.00 eq) from step 4.2, 318 mg 2-iodoacetamide (1.72 mmol, 2.00 eq) and0.585 mL of DIPEA (3.35 mmol, 4.00 eq) in DMF (2 mL) was heated in amicrowave at 100° C. for 8 h. Then NaOH (1M) was added and the mixturewas extracted with dichloromethane. The organic phase was dried overMgSO₄ and reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-10% methanol in dichloromethane) toyield the title product (93%, 0.803 mmol).

ESI-MS: m/z (%): 267.15 (100, [M+H]⁺).

4.42-(4-(2,2-Difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 225 mg of2-(4-(2,2-difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide(0.845 mmol, 1.00 eq) from step 4.3 in THF (10 ml) was added 1.27 mL ofborane tetrahydrofurane complex (2 M in THF, 2.53 mmol, 3.00 eq). Themixture was heated in a microwave at 90° C. for 2 h. Then the reactionmixture was quenched with HCl (1 M) and the aqueous phase was extractedwith ethyl acetate. The organic phase was extracted three times with HCl(1M) and to the aqueous phase was added NaOH (1M) until pH 10 and wasthen extracted with dichloromethane three times. The organic phase wasdried over MgSO₄ and reduced under vacuum. The crude product waspurified by column chromatography on silica (eluent: 0-30% methanol indichloromethane) to yield the title product (64%, 0.543 mmol).

ESI-MS: m/z (%): 253.15 (100, [M+H]⁺).

4.58-(2,2-Difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 137 mg of2-(4-(2,2-difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine(0.543 mmol, 1.00 eq) from step 4.4, formaldehyde (0.570 mmol, 1.05 eq)and TFA (0.597 mmol, 1.10 eq) in ethanol (5 mL) was stirred at ambienttemperature for 24 h. Then NaOH (1M) was added and the mixture wasextracted with dichloromethane. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-10% methanol in dichloromethane) toyield the title product (64%, 0.346 mmol).

ESI-MS: m/z (%): 265.20 (100, [M+H]⁺).

¹H NMR (500 MHz, CDCl₃) of mixture of diastereomers: δ 7.21-7.13 (m,2H), 7.04-6.98 (m, 2H), 6.85 (t, J=7.5 Hz, 1H), 6.77 (t, J=7.5 Hz, 1H),3.96-3.88 (m, 4H), 3.39-3.17 (m, 4H), 3.15-3.08 (m, 8H), 2.63-2.53 (m,2H), 2.11-2.01 (m, 1H), 2.01-1.91 (m, 1H), 1.89-1.75 (m, 2H), 1.73-1.59(m, 3H), 1.53-1.43 (m, 1H), 1.42-1.34 (m, 1H), 1.14-1.05 (m, 1H). (NHnot detected)

4.6 Analytical separation of the 4 isomers of8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolineobtained in step 4.5

The Separation was Carried Out in Two Steps Via Method C:

Two peaks were separated on a Phenomenex LUX Amylose-2 Column (250×4.6mm, 5 μm) (t_(R) [min]=3.4, 4.1). The mobile phase consisted of 90% CO₂and 10% modifier. As modifier, MeOH with 0.2 Vol % of aqueous ammoniasolution (25%) was used. The first peak was then subjected to a secondseparation on a Daicel Chiralcel® OD-H column (100×4.6 mm, 5 μm) (t_(R)[min]=4.1, 4.6). The mobile phase consisted of 95% CO₂ and 5% modifier.As modifier, MeOH with 0.2 Vol % of aqueous ammonia solution (25%) wasused.

The second peak was separated on a Daicel Chiralpak® AD-H (100×4.6 mm, 5μm) (t_(R) [min]=3.7, 4.5). The mobile phase consisted of 95% CO₂ and 5%modifier. As modifier, MeOH with 0.2 Vol % of aqueous ammonia solution(25%) was used.

4.7 Preparative separation of the 4 isomers of8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolineobtained in step 4.5

The Separation of the 4 Isomers was Carried Out in Two Steps byUV-Detection at 214 Nm:

Two peaks were separated on a Phenomenex LUX Amylose-2 Column (250×21.2mm, 5 μm) (t_(R) [min]=3.1, 3.8). The mobile phase consisted of 90% CO₂and 10% modifier. As modifier, MeOH with 0.2 Vol % of aqueous ammoniasolution (25%) was used. The first peak was then subjected to a secondseparation on a Daicel Chiralcel® OD-H column (250×20 mm, 5 μm) (t_(R)[min]=9.2, 10.1). The mobile phase consisted of 95% CO₂ and 5% modifier.As modifier, MeOH with 0.2 Vol % of aqueous ammonia solution (25%) wasused.

The second peak was separated on a YMC CHIRAL Amylose-C column (250×20mm, 5 μm) (t_(R) [min]=7.1, 8.2). The mobile phase consisted of 95% CO₂and 5% modifier. As modifier, MeOH with 0.1 Vol % diethylamine was used.

Isomer 4.A of8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolone(single enantiomer of the compound of example 4.5)

ESI-MS: m/z (%): 265.20 (100, [M+H]⁺).

The retention time according to the analytical method described above is4.6 min and according to the preparative method described above 9.2 min.

Isomer 4.B of8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolone(single enantiomer of the compound of example 4.5)

ESI-MS: m/z (%): 265.20 (100, [M+H]⁺).

The retention time according to the analytical method described above is4.6 min and according to the preparative method described above 10.1min.

Isomer 4.0 of8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolone(single enantiomer of the compound of example 4.5)

ESI-MS: m/z (%): 265.20 (100, [M+H]⁺).

The retention time according to the analytical method described above is3.7 min and according to the preparative method described above method7.1 min.

Isomer 4.D of8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolone(single enantiomer of the compound of example 4.5)

ESI-MS: m/z (%): 265.20 (100, [M+H]⁺).

The retention time according to the analytical method described above is4.5 min and according to the preparative method described above 8.2 min.

Example 58-(Oxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(compound Ia.1 wherein R⁶ is oxetan-3-yl and R^(4a), R^(4b), R^(5a),R^(5b) and R^(3a) are hydrogen) 5.14-(Oxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one

A mixture of 750 mg of oxetan-3-yl-acrylic acid ethyl ester (2.40 mmol,1.00 eq), 658 mg of 2-aminophenyl boronic ester (4.80 mmol, 2.00 eq),664 mg of potassium carbonate (4.80 mmol, 2.00 eq) and 54.8 mg of[RhOH(COD)]₂ (0.120 mmol, 0.05 eq) in 2% wt. TPGS-750-M solution inwater (15 mL) was stirred vigorously at ambient temperature for the 48h. Then the reaction mixture was extracted with ethyl acetate. Theorganic phase was dried over MgSO₄, filtrated and reduced under vacuum.The crude product was purified by column chromatography on silica(eluent: 0-10% methanol in dichloromethane) to yield the title product(90%, 2.17 mmol).

ESI-MS: m/z (%): 204.10 (100, [M+H]⁺).

5.2 4-(Oxetan-3-yl)-1,2,3,4-tetrahydroquinoline

To a solution of 882 mg of 4-(oxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one(2.17 mmol, 1.00 eq) from step 5.1 in THF (20 ml) 6.51 mL of lithiumaluminium hydride (1 M in THF, 6.51 mmol, 3.00 eq) was slowly added at0° C. The mixture was stirred at 0° C. for 10 min and was then warmed upto room temperature and stirred for further 6 h at room temperature.Then the mixture was cooled to 0° C. and water (0.03 mL) was addedfollowed by 10% aqueous NaOH (0.03 mL) and water (0.1 mL) again. Themixture was stirred at 0° C. for 1 h. Then MgSO₄ was added and themixture was filtrated and the solvent was evaporated. The crude productwas purified by column chromatography on silica (eluent: 0-10% methanolin dichloromethane) to yield the title product (13%, 0.301 mmol).

ESI-MS: m/z (%): 190.20 (100, [M+H]⁺).

5.3 2-(4-(Oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 57 mg of 4-(oxetan-3-yl)-1,2,3,4-tetrahydroquinoline (0.301mmol, 1.00 eq) from step 5.2, 111 mg of 2-iodoacetamide (0.602 mmol,2.00 eq) and 0.205 mL of DIPEA (1.20 mmol, 4.00 eq) in DMF (1 mL) washeated in a microwave at 100° C. for 16 h. Then NaOH (1M) was added andthe mixture was extracted with dichloromethane. The organic phase wasdried over MgSO₄ and reduced under vacuum. The crude product waspurified by column chromatography on silica (eluent: 0-10% methanol indichloromethane) to yield the title product (55%, 0.166 mmol).

ESI-MS: m/z (%): 247.20 (100, [M+H]⁺).

5.4 2-(4-(Oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 41 mg of2-(4-(oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide (0.166 mmol,1.00 eq) from step 5.3 in THF (4 ml) 0.499 mL of lithium aluminiumhydride (1 M in THF, 0.499 mmol, 3.00 eq) was slowly added at 0° C. Themixture was stirred at 0° C. for 10 min and was then warmed up to roomtemperature and stirred for further 6 h at room temperature. Then themixture was cooled to 0° C. and water (0.03 mL) was added followed by10% aqueous NaOH (0.03 mL) and water (0.1 mL) again. The mixture wasstirred at 0° C. for 1 h. Then MgSO₄ was added and the mixture wasfiltrated and the solvent was evaporated. The crude product was purifiedby column chromatography on silica (eluent: 0-10% methanol indichloromethane) to yield the title product (38%, 0.064 mmol).

ESI-MS: m/z (%): 233.20 (100, [M+H]⁺).

5.58-(Oxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 86 mg of2-(4-(oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine (0.370 mmol,1.00 eq) from step 5.4, formaldehyde (0.389 mmol, 1.05 eq) and TFA(0.407 mmol, 1.10 eq) in ethanol (3 mL) was stirred at ambienttemperature for 2 h. Then NaOH (1M) was added and the mixture wasextracted with dichloromethane. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by SFC to yieldthe title product (3.5%, 0.013 mmol).

ESI-MS: m/z (%): 245.30 (100, [M+H]⁺).

¹H NMR (500 MHz, Methanol-d₄): δ 6.97 (d, J=7.3, 1.4 Hz, 1H), 6.79 (d,J=7.4 Hz, 1H), 6.70 (t, J=7.5 Hz, 1H), 4.90-4.80 (m, 1H), 4.79-4.70 (m,2H), 4.68-4.60 (m, 1H), 3.79 (q, J=14.0 Hz, 2H), 3.36-3.27 (m, 2H),3.27-3.17 (m, 2H), 3.20-3.06 (m, 3H), 3.05-2.92 (m, 2H), 1.94-1.84 (m,1H), 1.67-1.57 (m, 1H).

Example 68-(Tetrahydro-2H-pyran-4-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(compound Ia.1 wherein R⁶ is tetrahydro-2H-pyran-4-yl and R^(4a),R^(4b), R^(5a), R^(5b) and R^(7a) are hydrogen) 6.14-(Tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-2(1H)-one

A mixture of 100 mg of tetrahydropyran-4-yl-acrylic acid ethyl ester(0.588 mmol, 1.00 eq), 161 mg of 2-aminophenyl boronic ester (1.18 mmol,2.00 eq), 162 mg of potassium carbonate (1.18 mmol, 2.00 eq) and 13.4 mgof [RhOH(COD)]₂ (0.029 mmol, 0.05 eq) in 2% wt. TPGS-750-M solution inwater (3 mL) was stirred vigorously at ambient temperature for 48 h andthen at 70° C. for further 20 h. The reaction mixture was extracted withethyl acetate. The organic phase was dried over MgSO₄, filtrated andreduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-20% methanol in dichloromethane) toyield the title product (67%, 0.395 mmol).

ESI-MS: m/z (%): 232.20 (100, [M+H]⁺).

6.2 4-(Tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline

To a solution of 91.4 mg of4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.395 mmol,1.00 eq) from step 6.1 in THF (2 ml) was added 0.790 mL of boranetetrahydrofurane complex (2 M in THF, 1.58 mmol, 4.00 eq). The mixturewas stirred at room temperature for 16 h and then heated in a microwaveat 90° C. for 2 h. Then the reaction mixture was quenched with HCl (1 M)and the aqueous phase was extracted with ethyl acetate. The organicphase was extracted three times with HCl (1M) and to the aqueous phasewas added NaOH (1M) until pH 10 and was then extracted withdichloromethane three times. The organic phase was dried over MgSO₄ andreduced under vacuum to yield the title product (44%, 0.173 mmol).

ESI-MS: m/z (%): 218.20 (100, [M+H]⁺).

6.32-(4-(Tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 37.6 mg of4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline (0.173 mmol,1.00 eq) from step 6.2, 128 mg of 2-iodoacetamide (0.692 mmol, 4.00 eq)and 0.177 mL of DIPEA (1.04 mmol, 6.00 eq) in DMF (3 mL) was heated in amicrowave at 120° C. for 8 h. Then NaOH (1M) was added and the mixturewas extracted with dichloromethane. The organic phase was dried overMgSO₄ and reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-30% methanol in dichloromethane) toyield the title product.

ESI-MS: m/z (%): 275.20 (100, [M+H]⁺).

6.42-(4-(Tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 191 mg of2-(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide(0.696 mmol, 1.00 eq) from step 6.3 in THF (5 ml) was added 1.74 mL ofborane tetrahydrofurane complex (2 M in THF, 3.48 mmol, 5.00 eq). Themixture was stirred at room temperature for 16 h and then heated in amicrowave at 90° C. for 1 h. Then the reaction mixture was quenched withHCl (1 M) and the aqueous phase was extracted with ethyl acetate. Theorganic phase was extracted three times with HCl (1M) and to the aqueousphase was added NaOH (1M) until pH 10 and was then extracted withdichloromethane three times. The organic phase was dried over MgSO₄ andreduced under vacuum to yield the title product (76%, 0.529 mmol).

ESI-MS: m/z (%): 261.20 (100, [M+H]⁺).

6.58-(Tetrahydro-2H-pyran-4-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 33.8 mg of2-(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine(0.130 mmol, 1.00 eq) from step 6.4, formaldehyde (0.130 mmol, 1.00 eq)and TFA (0.143 mmol, 1.10 eq) in ethanol (2 mL) was stirred at ambienttemperature for 48 h and then at 70° C. for further 4 h. The solvent wasremoved under vacuum. The residue was dissolved in DCM and washed withsaturated aqueous sodium bicarbonate solution. The organic layer wasdried over Na₂SO₄, filtrated and reduced under vacuum. The crude productwas purified by column chromatography on silica (eluent: 0-30% methanolin dichloromethane) to yield the title compound (15%, 0.019 mmol).

ESI-MS: m/z (%): 273.20 (100, [M+H]⁺).

¹H NMR (600 MHz, Methanol-d₄): δ 7.14 (td, J=7.4, 1.6 Hz, 2H), 6.85 (t,J=7.5 Hz, 1H), 4.29 (d, J=13.7 Hz, 1H), 4.17 (d, J=13.8 Hz, 1H),4.01-3.91 (m, 2H), 3.63 (s, 1H), 3.50-3.45 (m, 1H), 3.43-3.30 (m, 4H),3.26 (ddd, J=12.1, 10.4, 4.0 Hz, 1H), 2.66 (s, 1H), 2.63 (dt, J=7.9, 5.2Hz, 1H), 2.09-2.01 (m, 1H), 1.89-1.82 (m, 1H), 1.82-1.74 (m, 1H),1.61-1.55 (m, 1H), 1.55-1.49 (m, 2H), 1.39-1.27 (m, 1H). (NH notdetected)

Example 78-(Tetrahydrofuran-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(compound Ia.1 wherein R⁶ is tetrahydrofuran-3-yl and R^(4a), R^(4b),R^(5a), R^(5b) and R^(7a) are hydrogen) 7.14-(Tetrahydrofuran-3-yl)-3,4-dihydroquinolin-2(1H)-one

A mixture of 100 mg of tetrahydrofuran-3-yl-acrylic acid methyl ester(0.640 mmol, 1.00 eq), 175 mg of 2-aminophenyl boronic ester (1.28 mmol,2.00 eq), 177 mg of potassium carbonate (1.28 mmol, 2.00 eq) and 14.6 mgof [RhOH(COD)]₂ (0.032 mmol, 0.05 eq) in 2% wt. TPGS-750-M solution inwater (3 mL) was stirred vigorously at ambient temperature for the 48 hand then at 70° C. for further 6 h. The reaction mixture was extractedwith ethyl acetate. The organic phase was dried over MgSO₄, filtratedand reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-30% methanol in dichloromethane) toyield the title product (81%, 0.516 mmol).

ESI-MS: m/z (%): 218.20 (100, [M+H]⁺).

7.2 4-(Tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroquinoline

To a solution of 112 mg of4-(tetrahydrofuran-3-yl)-3,4-dihydroquinolin-2(1H)-one (0.516 mmol, 1.00eq) from step 7.1 in THF (2 ml) was added 1.03 mL of boranetetrahydrofurane complex (2 M in THF, 2.06 mmol, 4.00 eq). The mixturewas stirred at room temperature for 16 h and then heated in a microwaveat 90° C. for 2 h. Then the reaction mixture was quenched with HCl (1 M)and the aqueous phase was extracted with ethyl acetate. The organicphase was extracted three times with HCl (1M) and to the aqueous phasewas added NaOH (1M) until pH 10 and was then extracted withdichloromethane three times. The organic phase was dried over MgSO₄ andreduced under vacuum to yield the title product (69%, 0.358 mmol).

ESI-MS: m/z (%): 204.20 (100, [M+H]⁺).

7.3 2-(4-(Tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 72.7 mg of4-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroquinoline (0.358 mmol, 1.00eq) from step 7.2, 265 mg of 2-iodoacetamide (1.43 mmol, 4.00 eq) and0.367 mL of DIPEA (1.43 mmol, 6.00 eq) in DMF (3 mL) was heated in amicrowave at 120° C. for 8 h. Then NaOH (1M) was added and the mixturewas extracted with dichloromethane. The organic phase was dried overMgSO₄ and reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-70% methanol in dichloromethane) toyield the title product.

ESI-MS: m/z (%): 261.20 (100, [M+H]⁺).

7.4 2-(4-(Tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 480 mg of2-(4-(tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide (1.84mmol, 1.00 eq) from step 7.3 in THF (5 ml) was added 4.61 mL of boranetetrahydrofurane complex (2 M in THF, 9.22 mmol, 5.00 eq). The mixturewas stirred at room temperature for 16 h and then heated in a microwaveat 90° C. for 2 h. Then the reaction mixture was quenched with HCl (1 M)and the aqueous phase was extracted with ethyl acetate. The organicphase was extracted three times with HCl (1M) and to the aqueous phasewas added NaOH (1M) until pH 10 and was then extracted withdichloromethane three times. The organic phase was dried over MgSO₄ andreduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-70% methanol in dichloromethane) toyield the title product (12%, 0.215 mmol).

ESI-MS: m/z (%): 247.20 (100, [M+H]⁺).

7.58-(Tetrahydrofuran-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 53.0 mg of2-(4-(tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine(0.215 mmol, 1.00 eq) from step 7.4, formaldehyde (0.215 mmol, 1.00 eq)and TFA (0.237 mmol, 1.10 eq) in ethanol (2 mL) was stirred at ambienttemperature for 84 h. Then the solvent was removed under vacuum. Theresidue was dissolved with DCM and washed with saturated aqueous sodiumbicarbonate solution. The organic layer was dried over Na₂SO₄, filtratedand reduced under vacuum. The crude product was purified by preparativeHPLC to yield the title compound (38%, 0.082 mmol).

ESI-MS: m/z (%): 259.20 (100, [M+H]⁺).

¹H NMR of mixture of diastereomers (600 MHz, Methanol-d₄): δ 7.22-7.05(m, 4H), 6.87-6.79 (m, 2H), 4.30 (d, J=13.9 Hz, 2H), 4.16 (dd, J=13.8,4.4 Hz, 2H), 3.98-3.90 (m, 3H), 3.80-3.62 (m, 4H), 3.53-3.30 (m, 13H),2.82-2.71 (m, 2H), 2.60-2.43 (m, 2H), 2.17-2.09 (m, 1H), 2.04-1.97 (m,1H), 1.95-1.86 (m, 4H), 1.85-1.79 (m, 1H), 1.72-1.62 (m, 1H). (NH notdetected)

Example 88-Cyclopropyl-10-(2-methoxyethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(compound Ia.1 wherein R⁶ is cyclopropyl, R^(4a), R^(4b), R^(5a) andR^(5b) are hydrogen, and R^(7a) is 2-methoxyethyl) 8.1 tert-Butyl8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

A solution of 980 mg of8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(4.29 mmol, 1.00 eq) from example 1.6, 1.20 mL of triethylamine (8.58mmol, 2.00 eq) and 937 mg of di-tert-butyl dicarbonate (4.29 mmol, 1.00eq) in DCM (20 mL) was stirred 30 min at room temperature. Then theorganic phase was extracted with water, dried over MgSO₄ and the solventwas evaporated to yield the title compound (100%, 4.29 mmol).

ESI-MS: m/z (%): 329.20 (100, [M+H]⁺).

8.2 tert-Butyl10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

A solution of 600 mg of tert-butyl8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(1.83 mmol, 1.00 eq) from step 8.1 in THF (20 mL) was cooled to 0° C.Then 325 mg N-bromosuccinimide (1.83 mmol, 1.00 eq) was added and themixture was stirred for 30 min at 0° C. The solvent was evaporated toyield the title compound.

ESI-MS: m/z (%): 408.20 (100, [M+H]⁺).

8.3 tert-Butyl8-cyclopropyl-10-(2-methoxyethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

Under an argon atmosphere a mixture of 100 mg of tert-butyl10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(0.245 mmol, 1.00 eq) from step 8.2, 40.7 mg of potassium trifluoro(2-methoxyethyl)borate (0.245 mmol, 1.00 eq), 240 mg of cesium carbonate(0.736 mmol, 3.00 eq), 2.04 mg of Pd(OAc)₂ (0.009 mmol, 0.04 eq) and8.19 mg of X-Phos (0.017 mmol, 0.07 eq) in degassed THF (4 mL) and water(0.5 mL) was heated in a microwave at 120° C. for 20 h. Then the solventwas evaporated to yield the title compound.

ESI-MS: m/z (%): 387.30 (100, [M+H]⁺).

8.48-Cyclopropyl-10-(2-methoxyethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

To a solution of 100 mg of tert-Butyl8-cyclopropyl-10-(2-methoxyethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(0.259 mmol, 1.00 eq) in DCM (3 mL) was added 0.199 mL TFA (2.59 mmol,10.0 eq) and the mixture was stirred for 18 h at room temperature andthen at 70° C. for further 8 h. The solvent was evaporated and the crudeproduct was purified via preparative HPLC to yield the title compound(3.8%, 0.010 mmol).

ESI-MS: m/z (%): 287.30 (100, [M+H]⁺).

¹H NMR (500 MHz, Methanol-d₄): δ 7.36 (d, J=2.1 Hz, 1H), 7.03 (d, J=2.0Hz, 1H), 4.20 (d, J=1.8 Hz, 2H), 3.57 (t, J=6.7 Hz, 2H), 3.48-3.40 (m,1H), 3.35-3.25 (m, 5H), 3.32 (s, 3H), 2.78 (t, J=6.7 Hz, 2H), 2.09-2.01(m, 1H), 2.01-1.93 (m, 1H), 1.88-1.78 (m, 1H), 1.29 (s, 1H), 0.92-0.79(m, 1H), 0.74-0.66 (m, 1H), 0.55-0.43 (m, 2H), 0.29-0.20 (m, 1H).

Example 98-Cyclopropyl-10-(methoxymethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(compound Ia.1 wherein R⁶ is cyclopropyl, R^(4a), R^(4b), R^(5a) andR^(5b) are hydrogen, and R^(7a) is methoxymethyl) 9.1 tert-butyl8-cyclopropyl-10-(methoxymethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

Under an argon atmosphere a mixture of 70 mg of tert-butyl10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(0.172 mmol, 1.00 eq) from step 8.2, 52.2 mg of potassium trifluoro(2-methoxymethyl)borate (0.344 mmol, 2.00 eq), 168 mg of cesiumcarbonate (0.516 mmol, 3.00 eq), 1.43 mg of Pd(OAc)₂ (0.006 mmol, 0.04eq) and 5.73 mg of X-Phos (0.012 mmol, 0.07 eq) in degassed dioxane (4mL) and water (0.5 mL) was heated in a microwave at 130° C. for 40 h.Then the mixture was extracted with DCM and the organic phase was washedwith water and dried over MgSO₄, filtrated and solvent was evaporated toyield the title compound.

ESI-MS: m/z (%): 373.30 (100, [M+H]⁺).

9.28-cyclopropyl-10-(methoxymethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

To a solution of 51.6 mg of tert-butyl8-cyclopropyl-10-(methoxymethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(0.139 mmol, 1.00 eq) from step 9.2 in DCM (3 mL) was added 0.107 mL ofTFA (1.39 mmol, 10.0 eq) and the mixture was stirred for 48 h at roomtemperature. Then the solvent was evaporated and the crude product waspurified via preparative HPLC to yield the title compound (2.2%, 0.003mmol).

ESI-MS: m/z (%): 273.20 (100, [M+H]⁺).

Example 108-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-10-carbonitrile(compound Ia.1 wherein R⁶ is cyclopropyl, R^(4a), R^(4b), R^(5a) andR^(5b) are hydrogen, and R^(7a) is cyano) 10.1 tert-Butyl10-cyano-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

Under an argon atmosphere a mixture of 30 mg of tert-butyl10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(0.074 mmol, 1.00 eq) from step 8.2, 38.9 mg of potassiumhexacyanoferrate(II) trihydrate (0.092 mmol, 1.25 eq), 25.4 mg ofpotassium carbonate (0.184 mmol, 2.50 eq), 3.31 mg of Pd(OAc)₂ (0.015mmol, 0.20 eq) and 14.04 mg of X-Phos (0.029 mmol, 0.40 eq) in degasseddioxane (2 mL) and water (2 mL) was heated in a microwave at 100° C. for10 h. Then the mixture was extracted with DCM and the organic phase waswashed with water and dried over MgSO₄, filtrated and the solvent wasevaporated to yield the title compound.

ESI-MS: m/z (%): 354.30 (100, [M+H]⁺).

10.28-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-10-carbonitrile

To a solution of 33.6 mg of tert-butyl10-cyano-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(0.095 mmol, 1.00 eq) from step 10.1 in DCM (10 mL) was added 0.073 mLof TFA (0.951 mmol, 10.0 eq) and the mixture was stirred for 18 h atroom temperature and heated in a microwave for further 4 h at 50° C. andthen at 70° C. for further 3 h. The solvent was evaporated and the crudeproduct was purified via preparative HPLC to yield the title compound(10%, 0.009 mmol).

ESI-MS: m/z (%): 254.20 (100, [M+H]⁺).

¹H NMR (600 MHz, Methanol-d₄): δ 7.66 (dd, J=2.1, 0.9 Hz, 1H), 7.43 (d,J=2.0 Hz, 1H), 4.34 (s, 2H), 3.70-3.61 (m, 2H), 3.56-3.51 (m, 1H), 3.48(t, J=5.1 Hz, 2H), 3.41-3.36 (m, 1H), 2.08-2.03 (m, 1H), 2.02-1.98 (m,1H), 1.91-1.83 (m, 1H), 0.91-0.82 (m, 1H), 0.76-0.69 (m, 1H), 0.61-0.54(m, 1H), 0.48-0.40 (m, 1H), 0.31-0.24 (m, 1H). (NH not detected)

II. Biological Tests Functional Activity 1. Human 5-HT_(2C) FunctionalAssay

The functional activity of compounds of formula I was assayed byincubation with U2OS_HTR_(2C—)β-Arrestin cells (DiscoverX, 93-0289C3) toinduce beta-arrestin2 recruitment to the 5-HT_(2C) receptor. Theagonist-induced recruitment and proximity of the receptor andbeta-arrestin2 leads to complementation and formation of activeβ-galactosidase. The enzyme complementation results in enzyme activity,which is measured following the termination of the agonist incubationusing DiscoveRx's detection reagent, which contains a chemiluminescentsubstrate which produces a high intensity signal. Cells were plated anda medium-change to a 1% serum containing medium was performed 24 hlater. The next day, test compounds were added and incubated for 1.5 hbefore addition of detection reagent.

The response produced was measured and compared with the responseproduced by 10 [mu]M 5-HT or the maximal effect induced by 5-HT (definedas 100%) to which it was expressed as a percentage response (relativeefficacy). Dose response curves were constructed using Graphpad Prism(Graph Software Inc.) or using in house adapted software using a 4parameter dose response model with variable slope(fit=(Bottom+(Top-Bottom)/(1+10̂((Log EC50−x)*HillSlope))res=(y−fit)).Results are compiled in the table below.

2. Human 5-HT_(2A) Functional Assay

Functional activity on the 5-HT_(2A) receptor was determined by testingthe effect of the compounds I on calcium mobilisation in CHO-K1 cells,stably transfected with human 5-HT_(2A) receptor. Cells were seeded intosterile black 384-well plates with clear bottom at 25,000 cells/well ina volume of 25 μl and grown for 5-6 hours at 37° C., in 5% CO₂ in tissueculture medium (“Ultra CHO” by LONZA), containing 1% dialysed FCS and 50μg/ml gentamicin (Invitrogen). After this incubation, medium wasreplaced by a serum free version of the same tissue culture mediumfollowed by incubation overnight at 37° C. and in 5% CO₂. Cells werethen loaded with a fluorescent calcium-sensitive dye in the presence of0.07% probenecid for an hour at 37° C., according to the manufacturer'sprotocol (Ca5-Assay Kit, Molecular Devices), followed by an additional60 min incubation at room temperature. Serial compound dilutions (finalconcentrations of 10⁻¹⁰ to 10⁻⁵M, prepared in HBSS+50 mM HEPES) werefirst added to the cells alone (“first addition” to assess agonism onthe 5-HT_(2A) receptor), then after 8 min, serotonin was added to thesame wells at a final concentration of 3×10⁻⁸ M (“second addition” tosee potential antagonistic effect) and the maximal calcium response wasdetermined using a FLIPR® Tetra instrument (Molecular Devices) in eachof the two steps. The relative efficacy of the compounds was calculatedas a percentage of the maximal effect induced by serotonin alone(defined as 100%). To determine EC₅₀/IC₅₀ values, concentration-responsecurves were fitted using a four-parameter logistic equation (IDBSBiobook™). K_(b) values were calculated from IC₅₀ values, according toCheng & Prusoff.

3. Human 5-HT_(2B) Functional Assay

Functional activity on the 5-HT_(2B) receptor was determined by testingthe effect of the compounds I on calcium mobilisation in CHO-FlpIncells, stably transfected with human 5-HT_(2B) receptor. Cells wereseeded into sterile black 384-well plates with clear bottom at 30,000cells/well in a volume of 25 μl and grown overnight at 37° C., in 5% CO₂in tissue culture medium (“CHO-S-SFM II” by Invitrogen), containing 1%dialysed FCS and 50 μg/ml gentamicin (Invitrogen). On the next morning,medium was replaced by a serum free version of the same tissue culturemedium for a further incubation for 4 hours at 37° C. and in 5% CO₂.Cells were then loaded with a fluorescent calcium-sensitive dye in thepresence of 0.07% probenecid for an hour at 37° C., according to themanufacturer's protocol (Ca5-Assay Kit, Molecular Devices), followed byan additional 60 min incubation at room temperature. Serial compounddilutions (final concentrations of 10⁻¹⁰ to 10⁻⁵M, prepared in HBSS+50mM HEPES) were first added to the cells alone (“first addition” toassess agonism on the 5-HT_(2B) receptor), then after 8 min, serotoninwas added to the same wells at a final concentration of 10⁻⁸ M (“secondaddition” to see potential antagonistic effect) and the maximal calciumresponse was determined using a FLIPR® Tetra instrument (MolecularDevices) in each of the two steps. The relative efficacy of thecompounds was calculated as a percentage of the maximal effect inducedby serotonin alone (defined as 100%). To determine EC₅₀/IC₅₀ values,concentration-response curves were fitted using a four-parameterlogistic equation (IDBS Biobook™). K_(b) values were calculated fromIC₅₀ values, according to Cheng & Prusoff.

TABLE EC50 % EC50 % Selectivity⁴ EC50 Selectivity⁵ # 5-HT_(2C) ¹efficacy 5-HT_(2A) ² efficacy (based on agonism) 5-HT_(2B) ³ (based onagonism) 1 +++ 105 + 25 122  * antagonist 1.A +++ 89 *  antagonist⁶ *antagonist 1.B +++ 121 ++ 50 23 * antagonist 2 ++ 54 * antagonist *antagonist 3 ++ 88 * antagonist *  full⁷ 4 ++ 88 ++ 19  6 * antagonist4.A ++ 85 * antagonist * full 4.B ++ 99 + 33 18 * antagonist 4.C ++ 80 *antagonist * antagonist 4.D ++ 111 ** 24 45 * antagonist 5 + 82 *antagonist * full ¹Potency (EC50 5-HT_(2C)) in functional assay ²Potency(EC50 5-HT_(2A)) in functional assay ³Potency (EC50 5-HT_(2B)) infunctional assay ⁴EC50 5-HT_(2A)/EC50 5-HT_(2C) ⁵EC50 5-HT_(2B)/EC505-HT_(2C) ⁶“antagonist” indicates functional antagonism with nomeasurable agonistic effect ⁷“full” indicates no measurable agonisticeffect at 10 μM (highest concentration in assay) Potency (EC50): * >10nM ** 1 μM to 10 μM + from 200 nM to <1 μM ++ from 20 nM to <200 nM +++<20 nM

We claim:
 1. A compound of the formula I

wherein R¹ is selected from the group consisting of hydrogen, cyano,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinatedC₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,fluorinated C₁-C₆-alkoxy, —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl and a 3-,4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated ormaximally unsaturated heterocyclic ring containing 1, 2, 3 or 4heteroatoms or heteroatom groups independently selected from N, O, S,NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups as ringmembers, where the cyclic moieties in the three last-mentioned radicalsmay be substituted with one or more substituents R¹⁰; each R² isindependently selected from the group consisting of cyano, nitro,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl,—CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-,5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatomgroups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S asring members, where the cyclic moieties in the six last-mentionedradicals may be substituted with one or more substituents R¹⁰; or tworadicals R² bound to the same carbon atom, together with the carbon atomthey are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated,partially unsaturated or maximally unsaturated ring, where the ring maycontain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groupsselected from O, S, N, SO, SO₂, C═O and C═S as ring members, and wherethe ring may be substituted with one or more substituents R¹⁰; R^(3a)and R^(3b), independently of each other, are selected from the groupconsisting of hydrogen, cyano, nitro, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinatedC₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, —CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-, 5-,6-, 7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatomgroups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S asring members, where the cyclic moieties in the six last-mentionedradicals may be substituted with one or more substituents R¹⁰; R^(4a)and R^(4b), independently of each other, are selected from the groupconsisting of hydrogen, cyano, nitro, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinatedC₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, —CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-, 5-,6-, 7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatomgroups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S asring members, where the cyclic moieties in the six last-mentionedradicals may be substituted with one or more substituents R¹⁰; or R^(4a)and R^(4b) form together a group ═O or ═S; or R^(4a) and R^(4b),together with the carbon atom they are bound to, form a 3-, 4-, 5-, 6-,7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring, where the ring may contain 1, 2, 3 or 4 heteroatoms orheteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═Sas ring members, and where the ring may be substituted with one or moresubstituents R¹⁰; R^(5a) and R^(5b), independently of each other, areselected from the group consisting of hydrogen, halogen, cyano, nitro,hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl,C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinatedC₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy,C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl,C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —NR^(11a)R^(11b),—CH₂NR^(11a)R^(11b), —NR^(11a)C(O)R⁹, —C(═O)R⁹, SO₂NR^(11a)R^(11b),C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl,phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-,6-, 7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatomgroups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S asring members, where the cyclic moieties in the six last-mentionedradicals may be substituted with one or more substituents R¹⁰; whereR^(5a) and R^(5b) are not simultaneously hydroxyl; or R^(5a) and R^(5b),together with the carbon atom they are bound to, form a 3-, 4-, 5-, 6-,7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring, where the ring may contain 1, 2, 3 or 4 heteroatoms orheteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═Sas ring members, and where the ring may be substituted with one or moresubstituents R¹⁰; R⁶ is a cyclic radical selected from the groupconsisting of C₃-C₆-cycloalkyl which may carry one or more radicals R⁸;and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturatedor maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4heteroatoms or heteroatom groups independently selected from N, O, S,NO, SO and SO₂, and optionally also 1 or 2 groups C═O and/or C═S, asring members, where the heterocyclic ring may be substituted with one ormore substituents R¹⁰; each R⁷ is independently selected from the groupconsisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinatedC₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl,fluorinated C₃-C₈-cycloalkenyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl,C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinatedC₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinatedC₁-C₆-alkylsulfonyl, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b),—NR^(11a)C(O)R⁹, —C(═O)R⁹, SO₂NR^(11a)R^(11b), C₁-C₆-alkylcarbonyloxy,fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl, phenoxy,phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-memberedsaturated, partially unsaturated or maximally unsaturated ringcontaining 1, 2, 3 or 4 heteroatoms or heteroatom groups independentlyselected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, wherethe cyclic moieties in the six last-mentioned radicals may besubstituted with one or more substituents R¹⁰; or two radicals R⁷ boundon neighboring carbon atoms, together with the carbon atoms they arebound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered partially unsaturatedor maximally unsaturated ring, where the ring may contain 1, 2, 3 or 4heteroatoms or heteroatom-containing groups selected from O, S, N, SO,SO₂, C═O and C═S as ring members, and where the ring may be substitutedwith one or more substituents R¹⁰; each R⁸ is independently selectedfrom the group consisting of halogen, cyano, hydroxyl, C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinatedC₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinatedC₁-C₆-alkoxy-C₁-C₄-alkyl, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b), phenyl,phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or8-membered saturated, partially unsaturated or maximally unsaturatedring containing 1, 2, 3 or 4 heteroatoms or heteroatom groupsindependently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ringmembers, where the cyclic moieties in the five last-mentioned radicalsmay be substituted with one or more substituents R¹⁰; or two radicals R⁸bound to the same carbon atom may form together a group ═O or ═S; eachR⁹ is independently selected from the group consisting of hydrogen,cyano, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinatedC₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy,—NR^(11a)R^(11b), CH₂NR^(11a)R^(11b), phenyl, phenyl-C₁-C₂-alkyl,phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated,partially unsaturated or maximally unsaturated ring containing 1, 2, 3or 4 heteroatoms or heteroatom groups independently selected from N, O,S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moietiesin the five last-mentioned radicals may be substituted with one or moresubstituents R¹⁰; each R¹⁰ is independently selected from the groupconsisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinatedC₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinatedC₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy,C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl,C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —COOH,—NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b), C₁-C₆-alkylcarbonyl, fluorinatedC₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinatedC₁-C₆-alkoxycarbonyl, SO₂NR^(11a)R^(11b), C₁-C₆-alkylcarbonyloxy andfluorinated C₁-C₆-alkylcarbonyloxy; or two radicals R¹⁰, together withthe atom(s) they are bound to, form a saturated, partially unsaturatedor maximally unsaturated 3-, 4-, 5-, 6- or 7-membered carbocyclic orheterocyclic ring, where the heterocyclic ring contains 1, 2 or 3heteroatoms or heteroatom groups independently selected from N, O, S,NO, SO, SO₂, C═O and C═S as ring members; R^(11a) and R^(11b),independently of each other and independently of each occurrence, areselected from the group consisting of hydrogen, cyano, C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinatedC₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy,C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl,C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl, phenyl andbenzyl, where the phenyl moieties in the two last-mentioned radicals maycarry 1, 2 or 3 substituents selected from halogen, cyano nitro,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinatedC₁-C₆-alkoxy; or, if R^(11a) and R^(11b) are bound to the same nitrogenatom, together with this nitrogen atom may form a 3-, 4-, 5-, 6-, 7- or8-membered saturated, partially unsaturated or maximally unsaturatedheterocyclic ring, where the ring may further contain 1, 2, 3 or 4heteroatoms or heteroatom-containing groups selected from O, S, N, SO,SO₂, C═O and C═S as ring members, and where the ring may be substitutedwith one or more substituents selected from halogen, cyano nitro,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinatedC₁-C₆-alkoxy; a is 0, 1 or 2; and b is 0, 1, 2 or 3; or an N-oxide, atautomeric form, a stereoisomer or a pharmaceutically acceptable saltthereof.
 2. The compound as claimed in claim 1, where R¹ is selectedfrom hydrogen and C₁-C₆-alkyl.
 3. The compound as claimed in claim 2,where R¹ is hydrogen.
 4. The compound as claimed in any of the precedingclaims, where R² is selected from C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl. 5.The compound as claimed in claim 4, where R² is selected fromC₁-C₆-alkyl and fluorinated C₁-C₆-alkyl.
 6. The compound as claimed inclaim 5, where R² is selected from methyl and CF₃.
 7. The compound asclaimed in any of the preceding claims, where R^(3a) and R^(3b),independently of each other, are selected from hydrogen, cyano, nitro,C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl.
 8. The compound as claimed inclaim 7, where R^(3a) is selected from hydrogen, cyano, nitro,C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl; and R^(3b) is hydrogen.
 9. Thecompound as claimed in claim 8, where R^(3a) is selected from hydrogenand methyl; and R^(3b) is hydrogen.
 10. The compound as claimed in claim9, where R^(3a) and R^(3b) are hydrogen.
 11. The compound as claimed inany of the preceding claims, where R^(4a) and R^(4b), independently ofeach other, are selected from hydrogen, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinatedC₁-C₄-alkoxy-C₁-C₄-alkyl, or form together a group ═O, or form togethera group —(CH₂)_(m)—, where m is 2, 3 or
 4. 12. The compound as claimedin claim 11, where R^(4a) and R^(4b) are hydrogen.
 13. The compound asclaimed in any of the preceding claims, where R^(5a) is selected fromhydrogen, halogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl andC₁-C₆-alkoxy-C₁-C₄-alkyl and R^(5b) is hydrogen.
 14. The compound asclaimed in claim 13, where R^(5a) is hydrogen or methyl and R^(5b) ishydrogen.
 15. The compound as claimed in any of the preceding claims,where R⁶ is C₃-C₆-cycloalkyl which may carry one or more radicals R⁸;where R⁸ is as defined in claim
 1. 16. The compound as claimed in claim15, where each R⁸ is independently selected from the group consisting ofhalogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl. 17.The compound as claimed in any of claim 15 or 16, where R⁶ is selectedfrom cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl and 3,3-difluorocyclobutyl.
 18. The compound asclaimed in claim 17, where R⁶ is selected from cyclopropyl andcyclobutyl.
 19. The compound as claimed in claim 18, where R⁶ iscyclopropyl.
 20. The compound as claimed in claim 17, where R⁶ is2,2-difluorocyclopropyl.
 21. The compound as claimed in any of claims 1to 14, where R⁶ is a 3-, 4-, 5-, 6- or 7-membered saturated heterocyclicring containing 1, 2 or 3 heteroatoms or heteroatom groups independentlyselected from N, O, S, NO, SO and SO₂, and optionally also 1 or 2 groupsC═O and/or C═S, as ring members, where the heterocyclic ring may besubstituted with one or more substituents R¹⁰; where R¹⁰ is as definedin claim
 1. 22. The compound as claimed in claim 21, where R⁶ is a 3-,4-, 5- or 6-membered saturated heterocyclic ring containing 1 or 2heteroatoms or heteroatom groups independently selected from N, O, S,NO, SO and SO₂ as ring members, where the heterocyclic ring may besubstituted with one or more substituents R¹⁰; where R¹⁰ is as definedin claim
 1. 23. The compound as claimed in claim 22, where R⁶ is a4-membered saturated heterocyclic ring containing 1 heteroatom orheteroatom group selected from N, O, S, NO, SO and SO₂ as ring member,where the heterocyclic ring may be substituted with one or moresubstituents R¹⁰; where R¹⁰ is as defined in claim
 1. 24. The compoundas claimed in claim 23, where R⁶ is a 4-membered saturated heterocyclicring containing an oxygen atom as ring member, where the heterocyclicring may be substituted with one or more substituents R¹⁰; where R¹⁰ isas defined in claim
 1. 25. The compound as claimed in claim 24, where R⁶is oxetan-3-yl which may be substituted with one or more substituentsR¹⁰; where R¹⁰ is as defined in claim
 1. 26. The compound as claimed inclaim 22, where R⁶ is a 5- or 6-membered saturated heterocyclic ringcontaining 1 heteroatom or heteroatom group selected from N, O, S, NO,SO and SO₂ as ring member, where the heterocyclic ring may besubstituted with one or more substituents R¹⁰; where R¹⁰ is as definedin claim
 1. 27. The compound as claimed in claim 26, where R⁶ is a 5- or6-membered saturated heterocyclic ring containing an oxygen atom as ringmember, where the heterocyclic ring may be substituted with one or moresubstituents R¹⁰; where R¹⁰ is as defined in claim
 1. 28. The compoundas claimed in claim 27, where R⁶ is tetrahydrofuran-3-yl ortetrahydropyran-4-yl which may be substituted with one or moresubstituents R¹⁰; where R¹⁰ is as defined in claim
 1. 29. The compoundas claimed in any of claims 21 to 28, where R¹⁰ is selected from thegroup consisting of halogen, C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl.30. The compound as claimed in claim 29, where R¹⁰ is methyl.
 31. Thecompound as claimed in any of the preceding claims, where each R⁷ isindependently selected from the group consisting of halogen, cyano,nitro, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl,fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy andfluorinated C₁-C₆-alkoxy.
 32. The compound as claimed in claim 31, whereeach R⁷ is independently selected from halogen, C₁-C₄-alkyl, fluorinatedC₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinated C₁-C₄-alkoxy.
 33. The compoundas claimed in claim 32, where R⁷ is fluorine.
 34. The compound asclaimed in any of claims 1 to 31, where each R⁷ is independentlyselected from the group consisting of cyano andC₁-C₄-alkoxy-C₁-C4-alkyl.
 35. The compound as claimed in any of thepreceding claims, where a is 0 or
 1. 36. The compound as claimed inclaim 35, where in case that a is 1, R² is bound in β-position to thenitrogen ring atom carrying R¹.
 37. The compound as claimed in any ofthe preceding claims, where b is 0 or
 1. 38. The compound as claimed inany of the preceding claims, of formula I.1

wherein R², R⁶, R⁷ and b are as defined in any of claims 1, 4 to 6, 15to 34 and 37 and a is 0 or
 1. 39. The compound as claimed in claim 38,of formula I.1.1

wherein R^(7a) is H, Cl, F or methyl; a is 0 or 1; and R², R⁶, R⁷ and bare as defined in any of claims 1, 4 to 6, 15 to 34 and
 37. 40. Acompound selected from the group consisting of8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;(R)-8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;(S)-8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;(R)-8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;(S)-8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-(3-Methyloxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-(2,2-Difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-(Oxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-(Tetrahydro-2H-pyran-4-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-(Tetrahydrofuran-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-Cyclopropyl-10-(2-methoxyethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-Cyclopropyl-10-(methoxymethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;and8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-10-carbonitrile;and stereoisomers and pharmaceutically acceptable salts thereof.
 41. Amethod for producing a compound of formula I according to claim 1wherein R¹, R^(4b) and R^(5b) are hydrogen and R², if present, is boundin β-position to the nitrogen ring atom carrying R¹ (compound I′),comprising following steps: reacting a quinoline compound 1 in which Xis a leaving group with a boron compound of R⁶ to the quinoline compound2 in the presence of a Pd catalyst; reacting the quinoline compound 2with benzyl bromide to the N-protected quinolinium compound 3; reducingthe quinolinium compound 3 to the N-protected1,2,3,4-tetrahydroquinoline compound 4; deprotecting the N-protected1,2,3,4-tetrahydroquinoline compound 4 to the1,2,3,4-tetrahydroquinoline compound 5; reacting the1,2,3,4-tetrahydroquinoline compound 5 with the 2-halogenoacetamide 6,wherein Y is Cl, Br or I, to the 1-acetamide-substituted1,2,3,4-tetrahydroquinoline compound 7; reducing the carbonyl group ofthe 1-acetamide-substituted 1,2,3,4-tetrahydroquinoline compound 7 tothe ethylamine-substituted tetrahydroquinoline compound 8; reacting 8with the aldehyde or ketone 9, wherein R^(3a) and R^(3b) are as definedin claim 1, but for nitro or cyano, in the presence of a strong acid toI′; or reacting 2 with the 2-halogenoacetamide 6 to 10, which is thenreduced to 7, which is further reacted as described above:


42. A method for producing a compound of formula I according to claim 1wherein R¹, R^(4a), R^(4b) and R^(5b) are hydrogen, and R², if present,is bound in β-position to the nitrogen ring atom carrying R¹ (compoundI″), comprising following steps: reacting the boronic acid 11 and theα,β-unsaturated ester 12 in the presence of a Rhodium catalyst to thedihydroquinolone 13; reducing the dihydroquinolone 13 to the1,2,3,4-tetrahydroquinoline 14; reacting the 1,2,3,4-tetrahydroquinoline14 with the 2-halogenoacetamide 6, wherein Y is Cl, Br or I, to the1-acetamide-substituted 1,2,3,4-tetrahydroquinoline compound 15;reducing the carbonyl group of the 1-acetamide-substituted1,2,3,4-tetrahydroquinoline compound 15 to the ethylamine-substitutedtetrahydroquinoline compound 16; and reacting 16 with the aldehyde orketone 9, wherein R^(3a) and R^(3b) are as defined in claim 1, but fornitro or cyano, in the presence of a strong acid to I″:


43. A pharmaceutical composition comprising a therapeutically effectiveamount of at least one compound as claimed in any of claims 1 to 40 oran N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof, in combination with at least onepharmaceutically acceptable carrier and/or auxiliary substance.
 44. Thecompound as claimed in any of claims 1 to 40 or an N-oxide, a tautomericform, a stereoisomer or a pharmaceutically acceptable salt thereof foruse as a medicament.
 45. The compound as claimed in any of claims 1 to40 or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the treatment of disorderswhich respond to the modulation of the 5-HT_(2C) receptor.
 46. The useof a compound as claimed in any of claims 1 to 40 or of an N-oxide, atautomeric form, a stereoisomer or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for the treatment ofdisorders which respond to the modulation of the 5-HT_(2C) receptor. 47.A method for treating disorders which respond to the modulation of the5-HT_(2C) receptor, which method comprises administering to a subject inneed thereof at least one compound as defined in any of claims 1 to 40or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof.
 48. The compound as claimed in claim 45 or theuse as claimed in claim 46 or the method as claimed in claim 47, wherethe disorders are selected from the group consisting of damage of thecentral nervous system, disorders of the central nervous system, eatingdisorders, ocular hypertension, cardiovascular disorders,gastrointestinal disorders and diabetes.
 49. The compound or the use orthe method as claimed in claim 48, where the disorders are selected fromthe group consisting of bipolar disorder, depression, atypicaldepression, mood episodes, adjustment disorders, anxiety, panicdisorders, post-traumatic syndrome, psychoses, schizophrenia, cognitivedeficits of schizophrenia, memory loss, dementia of aging, Alzheimer'sdisease, neuropsychiatric symptoms in Alzheimer's disease, behavioraldisorders associated with dementia, social phobia, mental disorders inchildhood, attention deficit hyperactivity disorder, organic mentaldisorders, autism, mutism, disruptive behavior disorder, impulse controldisorder, borderline personality disorder, obsessive compulsivedisorder, migraine and other conditions associated with cephalic pain orother pain, raised intracranial pressure, seizure disorders, epilepsy,substance use disorders, alcohol abuse, cocaine abuse, tobacco abuse,smoking cessation, sexual dysfunction/erectile dysfunction in males,sexual dysfunction in females, premenstrual syndrome, late luteal phasesyndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea,chronic fatigue syndrome, psoriasis, Parkinson's disease, psychosis inParkinson's disease, neuropsychiatric symptoms in Parkinson's disease,Lewy Body dementia, neuropsychiatric symptoms in Lewy Body dementia,spinal cord injury, trauma, stroke, pain, bladder dysfunction/urinaryincontinence, encephalitis, meningitis, eating disorders, obesity,bulimia, weight loss, anorexia nervosa, ocular hypertension,cardiovascular disorders, gastrointestinal disorders, diabetesinsipidus, diabetes mellitus, type I diabetes, type II diabetes, typeIII diabetes, diabetes secondary to pancreatic diseases, diabetesrelated to steroid use, diabetes complications, hyperglycemia andinsulin resistance.
 50. The compound or the use or the method as claimedin claim 49, where the disorders are selected from schizophrenia,depression, bipolar disorders, obesity, substance use disorders,neuropsychiatric symptoms in Alzheimer's disease and neuropsychiatricsymptoms in Parkinson's disease.